Apparatus and Process for Providing a Coiled Collagen Carrier

ABSTRACT

The present invention relates inter alia to an apparatus for providing a coiled collagen carrier. An apparatus according to the invention preferably comprises a device for applying moisture to a collagen carrier prior to coiling of the collagen carrier and a coiling device. The coiling device preferably comprises rotatable gripping means for gripping the collagen carrier along an edge and coiling the collagen carrier, and a support device supporting the collagen carrier while being coiled. In another aspect, the invention relates to a production facility wherein an apparatus according to invention is arranged.

TECHNICAL FIELD OF THE INVENTION

The present invention relates inter alia to an apparatus for providing acoiled collagen carrier. An apparatus according to the inventionpreferably comprises a device for applying moisture to a collagencarrier prior to coiling of the collagen carrier and a coiling device.The coiling device preferably comprises rotatable gripping means forgripping the collagen carrier along an edge and coiling the collagencarrier, and a support device supporting the collagen carrier whilebeing coiled. In another aspect, the invention relates to a productionfacility wherein an apparatus according to invention is arranged. In afurther aspect, the invention relates to a process for coiling acollagen carrier. The collagen carrier preferably comprises (i) acollagen layer and (ii) a coating layer comprising fibrinogen andthrombin, and the process comprises the sequential steps of humidifyingat least part of said collagen carrier, coiling said collagen carrierdrying the coiled collagen carrier, so as to provide a form-stablecoiled collagen carrier

The present invention also relates to a process for the preparation of arolled collagen carrier, or a compressed collagen carrier or a rolledcompressed collagen carrier.

In addition, the present invention relates to a rolled compressedcollagen carrier, said rolled compressed collagen carrier beingobtainable by said process.

BACKGROUND OF THE INVENTION

Medicated sponges are used during open surgery to stop local bleeding(hemostasis/haemostasis). They react upon contact with blood, other bodyfluids or saline to form a clot that glues the sponge to the tissuesurface and hemostasis is reached in a few minutes. Medicated spongesare sponges, such as a collagen carrier as defined below, such as acellulose sponge as disclosed in EP2052746.

Collagen has been used as a haemostatic agent for decades. A productthat combines the haemostatic features of fibrin glue with the asset ofcollagen as a carrier has been developed and manufactured under thetrademark TachoSil®. TachoSil® is a ready-to-use collagen carrier with acoating of the active components of fibrin glue: human fibrinogen andhuman thrombin. The product is described in WO 02/058 749, WO 02/070 594and WO 02/058 750.

TachoSil® contains fibrinogen and thrombin as a dried coating on thesurface of a collagen sponge. In contact with body fluids, e.g. blood,lymph or physiological saline solution the components of the coatingdissolve and partly diffuse into the wound surface. This is followed bythe fibrinogen-thrombin reaction which initiates the last phase ofphysiological blood coagulation. Fibrinogen is converted into fibrinmonomers which spontaneously polymerise to a fibrin clot, which holdsthe collagen sponge tightly to the wound surface.

TachoSil® has been sold since 2004 by Nycomed and is used in opensurgery for hemostasis and sealing. Traditionally open surgery usuallyrequires a long incision of the skin.

Contrary to open surgery, a minimally invasive procedure is anyprocedure (surgical or otherwise) that is less invasive than opensurgery used for the same purpose. Minimally invasive surgery (MIS)procedures are performed through one or more access orifices e.g. shortincisions (‘keyhole surgery’) or through natural body openings. Hence,MIS procedures require specially designed surgical instruments which areplaced through these access orifices. In abdominal surgery, the accessof the instruments is usually done through so-called trocars, which aremostly rigid tubes with a typical inner diameter of 5 to 12 mm. Thesmall size of the access orifices used in MIS restricts what can beinserted into the orifices. Therefore, all surgical tools and materialsused in MIS procedures must be of a size and condition that allow fortheir insertion through the access orifices and they need, of course, asall medical tools to be sterile. Hence, tools and materials are mostoften specially designed for use in MIS.

WO 97/21383 (Nycomed Arzneimittel GmbH) discloses a surgical instrumentcomprising an applicating member, wherein the applicating membercomprises a rodshaped portion so as to allow a sheet of surgicalmaterial such as, e.g. TachoComb® (coated equine collagensponge/Nycomed) to be rolled up to form a carpetlike roll of surgicalmaterial on the rod-shaped portion of the applicating member. However,this manual instrument for hand-rolling surgical materials, such ascollagen carriers, has several disadvantages as described below. WO02/058749 discloses the non-sterile insertion of TachoComb® into anendoscopic equipment, wherein the sample is flattened manually to beable to wrap it manually around a guiding “pin”. WO 02/058749 teachesthat the collagen product “has to stay flexible enough in dry conditionto be bent and rolled up” (p29, lines 19-20). Thus WO 02/058749 onlyrelates to manual (i.e. hand-rolled), non-sterile rolling of TachoComb®and further teaches that the rolling process must be “dry”. Onesignificant problem with the above methods which use an applicatingmember or guiding pin for hand-coiling the collagen carrier arises incase application of multiple rolled/coiled collagen carriers isnecessary in quick succession (e.g. either because one collagen carrieris insufficient to completely stop the bleeding, or due to an error inapplication of the first collagen carrier(s)). In this instance the sameapplicating member cannot be used to apply the second collagen carrier:instead, multiple applicating members must be prepared. This is becausein order to apply collagen-based products such as the TachoComb® productcorrectly, the applicating member must be completely dry in order toavoid activating the adhesive properties of the collagen carrier. If thecollagen carrier becomes prematurely wet by contacting a wet applicationmember or guiding pin, the carrier will stick to the applicatingmember/guiding pin and/or become an unusable sticky lump of material.Another way of rolling up collagen-based surgical sheets is for thesurgeon to use his/her hands in the same way as for rolling up acigarette, however for this and all the manually-rolled cases above therolled surgical product is not form-stable and is therefore moredifficult to manipulate in a controlled manner after insertion into thebody: the non-form-stable product may “spring open” in an uncontrolledway during the unrolling process and adhere incorrectly. This is aparticular issue for MIS surgery, where it is harder to manipulate theproduct once it is in the body as one only has indirect access to thesurgical sheet via endoscopic surgical instruments. One way of lesseningthe effect of the rolled collagen-based surgical product beingnon-form-stable is to tie the rolled product together with a suture,however this solution is only relevant where the coiled carrier in notunrolled in vivo but rather maintained in the patient in a coiled state(e.g. in a partial nephrectomy procedure).

For applications such as MIS there is thus a need to produce an improvedcoiled collagen-based surgical product, which has dimensions useful forMIS applications and useful properties for promoting coagulation andwound sealing, but which allows easy application of more than onecollagen carrier in quick succession and furthermore gives the surgeonimproved control of the complex process of moving the carrier to thedesired tissue site and applying it.

A further problem with all the above types of manual coiling processesfor collagen carriers is that the results are of course highly dependenton the skills of the individual medical practitioner carrying out thecoiling process, and therefore highly variable in reproducibility, andmay lead to a non-sterile product, un-even and thus un-reproduciblecoiling/rolling of the collagen carrier, and un-predictable loss ofcoating.

Thus, there exists a need in the art for a collagen carrier coated withhuman fibrinogen and human thrombin especially designed for use inminimally invasive surgery that is ready-to-use, maintains sterility,and which has an acceptable hemostatic and tissue sealing effectivenessand adhesive strength to living tissue, and also which allows easyapplication of more than one collagen carrier in quick succession forMIS techniques, and also allows the surgeon more control on applicationto the desired tissue during an MIS procedure in order to avoid adhesionof the collagen carrier to an incorrect site, would be advantageous.

Hence, a ready-to-use collagen carrier coated with human fibrinogen andhuman thrombin designed particularly for use in MIS, such as designed tofit an access tube and/or orifice in MIS, preferably such as to beinserted into endoscopic devices would be advantageous, and inparticular a ready-to-use collagen carrier coated with human fibrinogenand human thrombin having an acceptable hemostatic effectiveness,adhesive strength to living tissue and sterility that is ready-to-use inMIS, allows easy application of more than one collagen carrier in quicksuccession for MIS techniques, and also allows the surgeon more controlon application to the desired tissue during an MIS procedure in order toavoid adhesion of the collagen carrier at the incorrect site, would beadvantageous.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide an apparatus andprocess capable of providing a ready-to-use collagen carrier coated withhuman fibrinogen and human thrombin designed e.g. for use in minimallyinvasive surgery, such as designed preferably to be inserted intoendoscopic devices.

Thus, in a first aspect the present invention relates to an apparatusfor providing a coiled collagen carrier. The apparatus comprisespreferably

-   -   a device for applying moisture to a collagen carrier prior to        coiling of the collagen carrier,    -   a coiling device comprising        -   rotatable gripping means for gripping the collagen carrier            along an edge and coiling the collagen carrier, and        -   a support device supporting the collagen carrier while being            coiled.

In preferred embodiments, the invention relates an apparatus forproviding a coiled collagen carrier, the apparatus comprising

-   -   a device for applying moisture to a collagen carrier prior to        coiling of the collagen carrier,    -   a coiling device comprising        -   rotatable gripping means for gripping the collagen carrier            along an edge and coiling the collagen carrier, and        -   a support device for supporting the collagen carrier while            being coiled.

Preferably, the gripping device comprises a pair of elongated members,such as a pair of tweezers or pincers.

The support device may in some preferred embodiments also serve astorage purpose in the sense that the coiled collagen carrier may bestored and protected from mechanical influence in the support deviceprior to any further handling of the coiled collagen carrier. A lid maybe applied to the support device during storage to protect and preventthe coiled collagen carrier from falling out of the support device. Suchlids are installed e.g. after the coiled collagen carriers have beendried in e.g. a drying tunnel.

The support device may preferably be or comprise a cavity having abottom shaped as a segment of a cylinder and having at least one openend. The curved part of the cylinder segment extends preferably at least180°, such as extends 180°. In addition, the cavity may preferably bechannel-formed with two parallel side wall extending from the bottom.

Such a channel-shaped cavity may preferably have a generally “U”-shapedcross section, wherein the bottom of the cavity forms the curved part ofthe “U”-shaped cross-section and each side wall forming the straightparts of the “U”-shaped cross section.

An apparatus according to the present invention may preferably beadapted to move the pair of elongated member in reciprocating movement,so that the elongated members can be retracted after the collagencarrier has been coiled. The reciprocating movement is typically in adirection being aligned with an longitudinal extension of the elongatedmembers.

Preferred embodiments of the apparatus may further comprise acompressing device arranged to compress the moisturised collagen carrierprior to coiling of the moisturised collagen carrier. The compressingdevice may preferably comprise a pair of rollers arranged to compressthe moisturised collagen carrier prior to coiling of the moisturisedcollagen carrier.

Preferred embodiments of the apparatus may further comprise at least adrying means for drying one or more coiled collagen carrierssubsequently to the coiling. The means for drying is preferably designedto dry off the moisture applied to the collagen carrier prior tocoiling. The at least one drying means may preferably comprise a dryingtunnel through which the coiled collaged carriers are conveyed whilebeing present in the support device.

The drying means may preferably comprise a pump sucking or blowing air,preferably being sterile filtered. The air pumped or sucked ispreferably sucked or pumped through the drying tunnel and thetemperature of the air may preferably be higher than the temperature ofthe coiled collagen carrier. In addition, means for applying heat insidethe drying tunnel may preferably be applied. In some preferredembodiments, the air sucked or blown is air from the surroundings of theapparatus, which often means that the air used is the air present in theroom where the apparatus for coiling a collagen carrier is located andthat air is used without any pre-conditioning such as heating, cooling,sterilization etc. The direction of the air being sucked or blown thoughthe drying tunnel may preferably be counter current to the conveyingdirection of the coiled collagen carriers or is in the same direction asthe conveying direction of the coiled collagen carriers. In somepreferred embodiments, the air being sucked or blown is sucked and blownin both directions. In the latter case, the suction or blowing is donethrough a opening arranged midway downstream of the drying tunnel andthe air escaping (when blowing) or entering (when sucking) through theopens ends of the drying tunnel.

Preferred embodiments of the apparatus according to the invention maypreferably comprise a first conveyer device which conveys collagencarriers prior to coiling past the moisturiser device and to the coilingdevice.

Preferred embodiments of the apparatus according to the invention maypreferably comprises a guide means for guiding and conveying thecollagen carrier from the device for applying moisture, through acompressing device (if present) and to a coiling device. By guiding ispreferably meant that the path the collagen carrier can follow isspatially restricted by the conveyer means of the guiding means.

In embodiments comprising a pair of rollers arranged to compress themoisturised collagen carrier prior to coiling of the moisturisedcollagen carrier, the first conveyer device conveys the moisturisedcollagen carriers to the pair of rollers. In general, the first conveyerdevice may convey the moisturised collagen carrier to the compressingdevice.

The first conveyer device may preferably comprise two conveyingelements, preferably in the form of two separate conveyer belts. Oneelement is adapted to convey the collagen carrier towards themoisturiser device and a second conveying element for conveying thecollagen carrier past the moisturiser device and towards the pair ofrollers or compression device.

Guide means may be present for guiding the humidified collagen carrierthrough a compression device, if present, and to the coiling device.

The cavity of the supporting device may preferably be formed in a secondconveyer device of the apparatus. Alternatively or in combinationthereto, the cavity of the supporting device may be formed in a trayhaving a plurality of cavities, said tray being arranged on and conveyedby a second conveyer device of the apparatus.

According to preferred embodiments of the invention, the apparatus maypreferably comprise a cabinet sealing the moisturiser device, and/or therollers, and/or the coiling device, and/or the support device, and/orthe first and/or the second conveyer device. By sealing is preferablymeant that the cabinet prevents some moisture from leaking to thesurrounding of the apparatus. In addition or alternatively thereto, theapparatus may further comprise suction means for sucking out gas and/ordroplets originating from the humidification. This preferably includesthat a chamber in which the collagen carrier is humidified and coiled aswell as the drying tunnel comprises openings allowing air to be suckedin or blown out.

Preferred embodiments of the apparatus may further comprise a device forconveying a coiled collagen carrier from the supporting device andarranging it in an inner container. Such a device may be a numericallycontrolled robot.

To close the inner container, the apparatus may further comprise a coverarranging device arranging a cover to at least the opening of the innercontainer.

In some preferred embodiments, the cover is heat welded or glued to theinner container and the apparatus may further comprise a heat weldingdevice or a gluing device heat welding or gluing the cover to the innercontainer.

The cover is preferably gas and/or liquid permeable and the innercontainer with the cover forms a closed inner container to be arrangedin a outer container. Preferred embodiments of the apparatus may furthercomprise a device arranging the inner container in an outer container.

In some preferred embodiments, the outer container is closed by heatwelding or gluing and the apparatus may further comprise a heat weldingdevice or a gluing device closing the outer container by heat welding orgluing.

The apparatus may further comprise a device for arranging a desiccantinside the outer container and outside the inner container for providinga packed coiled collagen carrier; e.g. a coiled collagen carrierarranged inside an inner container with cover which together with adesiccant is arranged inside and outer container.

The device(s) for conveying and/or arranging the coiled collagencarrier, the cover, the desiccant and/or the inner container maypreferably be a numerically controlled robot arm with gripping means.

Preferably, the apparatus may comprise a sterilizing device arranged tosterilize the packed coiled collagen carrier. The apparatus may furthercomprise sterilizing devices for sterilizing the collagen carrier atother steps of the production, e.g. for sterilizing the coiled collagencarrier when arranger in the inner container with cover. Preferably, thesterilizing device comprises a source of radio magnetic radiation.Alternatively, the sterilizing may be performed remote from theapparatus, e.g. by shipping the collagen carriers either being packed ornot packed to a sterilization department remote from the production sitefor coiled collagen carriers.

An apparatus according to the present invention, may further compriseone or more image recognition devices adapted to image the processing ofthe apparatus at preselected stages, examine the images and signal adiscard signal for a coiled collagen carrier in case the examiningreveals that a coiled collagen carrier falls outside quality ranges.

An apparatus according to the present invention may further comprise oneor more air-conditioning devices maintaining the atmosphere surroundingthe collagen carrier and humidification device while being humidifiedcompressed and coiled at a temperature of 18-22° C. and a relativehumidity of 30-50%.

In a second aspect the invention relates to a production facilitywherein different elements or parts of an apparatus according to thepresent invention are spatially distributed in a preferred manner.

Preferably, the elements or parts of an apparatus according to thepresent invention providing the coiled collagen carrier arranged in aninner container with cover applied may be arranged in a primaryproduction room being sealed by airlocks.

In combination thereto, the elements or part of an apparatus accordingto the present invention packaging the inner container in a outercontainer with a desiccant may preferably be arranged in a secondaryproduction room sealed by airlocks. Preferably, the primary andsecondary production rooms are connected by a conveyer extending inbetween the two production rooms and comprising an airlock; the innercontainer being conveyed by the conveyer from the primary productionroom to the secondary production room.

In a third aspect, the invention relates to a process for coiling acoated carrier, the process utilises preferably an apparatus accordingto any of the preceding claims and the coated carrier comprising (i) acarrier layer and (ii) a coating layer comprising fibrinogen andthrombin, said process comprising the sequential steps of:

-   -   humidifying at least part of said coated carrier,    -   coiling said carrier    -   drying the coiled coated carrier,        so as to provide a form-stable coiled collagen carrier

The carrier may preferably comprise one or more of collagen, cellulose,oxidised regenerated cellulose, a woven mesh of oxidized, regeneratedcellulose with polyglactin 910 filaments. Furthermore, thecharacteristics of the carrier presented herein may constitute or atleast form part of the carrier. The coated carrier is preferably acollagen carrier as disclosed herein.

Drying is preferably considered to have been completed when the residualamount of the liquid used for humidifying (or other liquid substances)is lower than a preselected limit (please see below for preferred andacceptable residual amounts). It is noted that in many of the preferredembodiments, the drying requirement is implemented as a drying time toavoid time-consuming and/or destructive measurements of the actual valuefor the residual amount in coiled collagen carrier produced according tothe present invention.

In preferred embodiments of the process, at least the coating layer ofsaid collagen carrier is humidified. Preferably, the coating layer hasbeen humidified using a solvent. Thereby the coating is softened. Thecollagen carrier is often flexible and there is therefore often no needto soften the collagen part of the collagen carrier.

Preferably the collagen carrier is humidified on the coating layer by asolvent in an amount 1.2-10.75 mg/cm² surface of the coating layer.Preferably, the solvent comprises or consists of ethanol. Water isgenerally not preferred as solvent. Furthermore, as the collagen carriernot including the coating layer typically is soft it if often notnecessary or desired to humidify the collagen part of the collagencarrier.

In a process according to the present invention, the collagen carriermay be compressed subsequently to humidifying and prior to coiling witha compression ratio between 6-12. The compression ratio is typically andpreferably considered to be the ratio between the thickness of thecollagen carrier before and after compression. It is noted, that thecollagen carrier after it has been compressed may experience somerelaxation resulting in that the compressed collaged carrier may reverttowards its state before being compressed if left at rest with nofurther subsequent processing due to the flexible nature of the collagencarrier. In such cases, the thickness after compression is considered tobe either the thickness of the collagen carrier while being compressed,which often resembles the distance between the elements performing thecompression (such as the gap size between a pair of rollers), or thethickness of the compressed collagen carrier immediately after it hasbeen compressed.

A process according to the present invention may further comprise thestep of arranging the form-stable coiled collagen carrier in an innercontainer. Preferably, the process may subsequently comprise the step ofclosing the inner container by applying a cover to the inner container.Further, a process according to the present invention may comprise afurther subsequent step of arranging the inner container in an outercontainer, and sealing the outer container. In combination thereto, aprocess according to the present invention may comprise the step ofarranging a desiccant inside the outer container and outside the innercontainer.

The arrangement of the form-stable coiled collagen carrier in the innercontainer and closing inner container may preferably be performed in aprimary production room and the arrangement of the inner container in anouter container is performed in a secondary production room. The firstand the secondary production rooms may be connected with each other byan airlock and the closed inner container is transported from the firstto the second room via the airlock.

Further, a process according to the present invention may comprisearranging a desiccator inside the outer container prior to sealing ofthe container.

Preferred embodiments of the process according to the present inventionmay further comprise the step of sterilizing the coiled collagencarrier. The sterilizing step may preferably be carried out when theinner container with cover is arranged inside the outer containertogether with a desiccant and after the outer container has been closed.

A process according to the present invention is preferably is carriedout as an assembly-line process in which the collagen carrier isconveyed without intermediate storing between humidifying preferablyonly by ethanol and coiling and between coiling and drying offpreferably only ethanol.

The humidifying of the collagen carrier may preferably be performed whena humidified collagen carrier may proceed directly to coiling withoutany intermediate storing.

Definitions

Prior to discussing the present invention in further details, thefollowing terms and conventions will first be defined:

The term “collagen carrier” is in the present context any suitablecarrier comprising collagen that can have a coating layer thatcomprises/consist of a collagen layer and/or a coating layer. Thecollagen carrier can in one embodiment be rolled or coiled (the words“rolled” and “coiled” are used interchangeably herein). The coiledcollagen carrier of the present invention can in one embodiment be acompressed, coiled collagen carrier, or in another embodiment anunrolled version of a compressed, coiled collagen carrier. Preferably,the collagen carrier is a collagen sponge comprising or consistingessentially of collagen type I fibres and a coating. Although thecarrier material is preferably a collagen sponge which comprisescollagen type I material from mammalian, transgenic or recombinantsources, it can also comprise another type of collagen, for example oneor more of collagen type I, II, III, IV, VII and/or X. Preferably thecollagen carrier, such as a collagen sponge, is coated with the humancoagulation factors fibrinogen and thrombin and optionally alsoriboflavin (a yellow colouring agent used to aid in identifying theactive side of the collagen carrier). Thus in one embodiment of thepresent invention, the collagen carrier is a collagen sponge consistingessentially of collagen type I fibres and a coating of fibrinogen,thrombin and riboflavin. Fibrinogen and thrombin can for example behuman fibrinogen and thrombin, and can be purified from a naturalsource, or can alternatively be e.g. transgenic or recombinant humanfibrinogen and thrombin, or can be manufactured by other methods such ase.g. chemical synthesis. Fibrinogen and thrombin are preferably solid ormostly solid and in one embodiment can be human of origin. In anotherembodiment, at least one and more preferably both of the componentsfibrinogen and thrombin have the human amino acid sequence and can beproduced by recombinant technology, inclusion bodies or chemicalsynthesis. The thrombin and fibrinogen are in one embodiment dry, suchas containing less than 5% water, such as less than 4% water, such asless than 3% water, such as less than 2% water, such as less than 1%water, such as less than 0.8% water, such as less than 0.6% water, suchas less than 0.4% water, such as less than 0.2% water, such as less than0.1% water.

In one embodiment of the present invention, the collagen carriercomprises or consists of (i) a collagen layer and (ii) a coating layercomprising fibrinogen and optionally thrombin and optionally a colouringagent such as e.g. riboflavin. The collagen carrier may in an embodimentfurther comprise other peptides, such as other peptides capable ofcausing haemostasis.

In one embodiment of the present invention, the expressions collagensponge, collagen fleece, collagen patch or simply fleece or patch areterms that are used synonymously to mean a collagen carrier. A carriermay alternatively to collagen comprise a biodegradable co-polymer or apolymer such as a polyhyaluronic acid, polyhydroxy acid, e. g. lacticacid, glucolic acid, hydroxybutanoic acid, a cellulose, or gelatine.Another alternative carrier may be polyglactin 910, i.e. a synthetic,adsorbable copolymer of 90% glycolide (C₂H₂O₂) and 10% lactide (C₆H₈O₄);such as e.g. with molecular formula (C₂H₂O₂)_(m) and (C₃H₄O₂)_(n). Afurther alternative carrier may be equine collagen, such as e.g. nativeequine collagen extracted from sinews or tendons.

Thus, the collagen part of the collagen carrier can in one embodiment ofthe present invention be substituted with a non-collagen matrix that iscoated in the same way as for the collagen carrier as described herein,i.e. in one embodiment of the present invention is provided a carriercomprising or consisting of a non-collagen matrix coated with a coatingcomprising or consisting of fibrinogen and thrombin. One example of asuitable non-collagen matrix is a cellulose fabric. In one embodiment ofthe present invention, the non-collagen matrix is an oxidizedregenerated cellulose fabric sheet attached to a non-woven polyglactin910 felt.

However, it is preferably a collagen carrier preferably having a shapesuitable for a medicated sponge. In an embodiment of the invention, thecollagen carrier which is to undergo the coiling process of the presentinvention is identical to Tachosil® or TachoComb® available fromNycomed, such as described in WO 02/058 749, WO 02/070 594 and WO 02/058750.

A preferred collagen layer is preferably used to mean a collagen spongeproduced by the method according to the invention as disclosed in WO02/070594. The collagen layer used in the present invention preferablyfulfills at least one, such as at least two or at least three, of thefollowing criteria:

-   -   pH-value between 5.0 and 6.0,    -   lactic acid content at the most 5%,    -   ammonium content at the most 0.5%,    -   soluble protein content, calculated as albumin content, at the        most 0.5%,    -   sulphate ashes content at the most 1.0%,    -   heavy metal content at the most 20 ppm,    -   microbiological purity, at the most 103 CFU/g,    -   collagen content of 75% to 100%,    -   density of 1-10 mg/cm³, such as 2-7 mg/cm³,    -   elasticity module of 5-100 N/cm², such as 10-50 N/cm², and        wherein when isolating parts of the sponge, the sponge will have        the following properties:    -   elasticity module in the range of 5 to 100 N/cm²,    -   density in the range of 1 to 10 mg/cm³,    -   chamber diameter of more than 0.75 mm and less than 4 mm, or a        chamber diameter average of at most 3 mm.

Please note that the density of a collagen carrier is the density of thecollagen carrier excluding the coating layer.

Preferably the collagen layer fulfills at least the following:

-   -   pH-value between 5.0 and 6.0,    -   lactic acid content at the most 5%,    -   ammonium content at the most 0.5%,    -   soluble protein content, calculated as albumin content, at the        most 0.5%,    -   sulphate ashes content at the most 1.0%,    -   heavy metal content at the most 20 ppm,    -   microbiological purity, at the most 103 CFU/g,    -   collagen content of 75% to 100%,    -   density of 1-10 mg/cm³, such as 2-7 mg/cm³.

Further, the collagen layer is air and liquid tight in the sense that,once the collagen sponge is applied to a wound, it will not allow air orliquid to pass through the collagen layer. Liquids are absorbed in thelayer. This effect is primarily achieved due to the fact the collagenlayer has a three-dimensional structure with stacked chambers separatedand substantially totally enclosed by walls of collagen material, incontradiction to known collagen sponges which have a fibre structure.

In the present context, the term “chamber diameter” should be understoodas the largest straight-line wall-to-wall distance in a chamber, i. e.as the largest diagonal straight-line distance of a chamber. Thechambers may be of a polygonal shape, such as of an octagonal shape.Thus, when the carrier is cut, the chambers are divided and cut tocaverns.

It has been found that a chamber diameter of more than 0.75 mm and lessthan 4 mm, or a chamber diameter average of at most 3 mm, renders thecollagen sponge particularly useful for being coated with a fibrin gluepreparation. When the carrier is cut, the chambers are divided and cutto caverns. The preferably solid fibrinogen and the preferably solidthrombin is fixed to the collagen layer and most of it is present in thecaverns thus providing a substantially even distribution of thepreferably solid thrombin and preferably solid fibrinogen. Due to thisand the fixation, it is possible to introduce substantial amounts offibrinogen and thrombin on the carrier in contrast to the situationwhere liquid compositions of thrombin and fibrinogen are e. g. droppedor sprayed onto the material.

Each coated collagen carrier as well as the uncoated collagen layer isinspected visually for the “pore size distribution”—no pores wider than4 mm and deeper than 2 mm are allowed. These sizes are measured with aruler if necessary.

By fixation of the coating layer to the collagen layer is preferablymeant that the coating layer adheres through mechanical interactionsi.e. by inclusion onto the collagen carrier pore surface and within thecoating layer.

In a preferred embodiment of the present invention, the amount offibrinogen and thrombin/cm² in the coating layer can be:

-   -   Thrombin 1.3-2.7 IU/cm² and/or    -   Fibrinogen 3.6-7.4 mg/cm²

In an embodiment, the above mentioned amounts of fibrinogen andthrombin/cm² are identical to Tachosil® or TachoComb® available fromNycomed, such as described in WO 02/058 749, WO 02/070 594 and WO 02/058750.

By substantially even distribution of the solid thrombin and solidfibrinogen is meant that the coating layer is substantially evenlydistributed across the collagen layer meaning that local changes inthickness of the coating layer is observed visually by SEM crosssections i.e. the coating layer may be located on the surface andsometimes at a lower level in an open cell. There should not be anythrough-going cracks (fissures) on the coating layer.

In an embodiment a collagen carrier according to the present inventionmay have a size of 92-98 mm*46-50 mm*4-7 mm and this carrier is called alarge size collagen carrier and has the shape of a box of rectangularcross-section with all sides flat. Hence, the area of the largestrectangular cross-section is about 42.3-49.0 cm². In another embodimenta midi size collagen carrier according to the present invention is 46-49mm*46-50 mm*4-7 mm, and has the shape of a square box of quadrantcross-section. Hence, the area of the quadrant cross-section is about21.2-24.5 cm². A midi size collagen carrier according to the inventionis preferred. In yet another embodiment a mini size collagen carrieraccording to the invention is 28-33 mm*23-27 mm*4-7 mm, and has theshape of a box of rectangular cross-section with all sides flat. Hence,the area of the largest rectangular cross-section is about 6.4-8.9 cm².

In an embodiment of the invention, a collagen carrier has at least oneof the following physical properties, such as at least two of thefollowing physical properties, such as at least three of the followingphysical properties, such as at least four of the following physicalproperties: elasticity module in the range of 5-100 N/cm², density of1-10 mg/cm³, chamber diameter of more than 0.75 mm and less than 4 mmand/or having a chamber diameter average below 3 mm and evenlydistributed and fixed upon said collagen carrier solid fibrinogen andsolid thrombin. Please note that the density of a collagen carrier isthe density of the collagen carrier excluding the coating layer.

“Mechanically stable” is meant to refer to “form-stable”.

Form-stable as used in form-stable coiled collagen carrier is preferablyused to mean a coiled collagen carrier which maintains its geometricalshape without being fixated by constraining or constriction elements notforming part of the collagen carrier. For example, a form-stable coiledcollagen carrier may maintain its geometrical shape because the coatinglayer and/or the collagen layer has no tension acting to distort—such asuncoil—the coiled collagen carrier. A further characteristic ofform-stable is that the coiled collagen carrier may be elastic deformedand revert to the shape it had before being elastic deformed byreleasing the tension provided by the elastic deformation. A furthercharacteristic of a form-stable coiled collagen carrier is that it ispreferably hardened in the coiled shape.

Solid as used e.g. solid fibrinogen and solid thrombin is used in amanner being ordinary to the skilled person to mean a material in solidstate. Mostly solid is preferably used to that a minor fraction of thematerial in question may be in a state being different from solid state(such as less than 5%, such as less than 3%, preferably less than 1%,such as less than 0.5%). Alternatively, mostly solid is preferably usedto mean that the material in question may contain liquid, such as lessthan 5% liquid, or less than 1% liquid.

According to some preferred embodiments, the coiled collagen carrier mayhave a water content up to 8% and an ethanol content up to 1.6% afterthe coiled collagen carrier has been dried.

By the term “rolling” is meant any well known process for rolling anobject i.e. by hand, mechanically or by a combination thereof.

Coiling as used e.g. in coiling said collagen carrier is preferably usedto mean the process of winding the collagen carrier into an elementpreferably having spiral shaped cross sections. The coiled collagencarrier may have an S-shaped core.

In one embodiment according to the invention, when a collagen carrier ismechanically rolled, the process for rolling comprises the steps ofgripping at least one outer edge of a collagen carrier by using at leastone gripping device, such as tweezers, such as mechanical fingers, andcoiling said at least one gripping device around its centre axis andthereby also coiling said collagen carrier, and releasing saidmechanically rolled collagen carrier from said at least one grippingdevice.

The process for rolling a collagen carrier according to the inventionalso comprises rolling preferably a compressed collagen carrier, such asan at least partly mechanically compressed collagen carrier, such as ahumidified collagen carrier, such as a humidified compressed collagencarrier. Hence, the rolling can be applied to any collagen carrier, suchas a medicated sponge, which is used directly without being previouslyexposed to one or more physical manipulations such as e.g.humidification, compression, elevated room temperature and humidity orgamma radiation. Preferably, the rolling process can be applied to anycollagen carrier which has been previously exposed to one or more ofsaid physical manipulations. In the present context the words to roll,spool, rotate or spin are used interchangeably.

By the term “compressed collagen carrier” is preferably meant acompressed collagen carrier, which has been subjected to an evenlydistributed pressure (i.e. compression) to achieve the followingphysical properties: a coating comprising solid fibrinogen and solidthrombin that is evenly distributed and fixed upon said collagencarrier, and having at least one of the following physical properties inthe unrolled state:

-   -   I. a thickness of at the most 4 mm    -   II. a sterility assurance level (SAL) of 10⁻⁶.

In one embodiment of the present invention, said compressed collagencarrier has optionally been humidified either before or optionally afterthe compression step to at least one side of said collagen carrier. Saidcompressed collagen carrier has optionally been at least partlymechanically processed.

By the term “compressing” is meant the process for compressing an objectsuch as a collagen carrier and it refers in the present context to theprocess when the collagen carrier when being compressed is subjected toan evenly distributed pressure. The words compression or compaction areused interchangeably. Likewise, the expressions explaining that anobject can be compressed, pressed or compacted are used interchangeablyherein. The collagen carrier can e.g. become compressed when it passesthrough a set of rollers using a certain gap size. The collagen carrierbeing pressed is preferably a humidified collagen carrier or anon-humidified collagen carrier. The use of a roller compactor ispreferred (mechanical compression). Hence, a compression can be made byany conventional manual or mechanical way of compressing an object bysubjecting it to an evenly distributed pressure i.e. preferably bypassing it through a set of rollers by roller compaction, by placing thecarrier between two sets of even/flat plates where the top plate is aplunger, or rolling a cylindrical object over said carrier which isplaced on a flat, even bottom plate.

The expression “gap size” refers in the present context to the shortestdistance measured in mm between the rollers in a roller compactor.Preferably, the compression is performed by roller compaction using agap size between the rollers of no more than 0.30 mm, such as no morethan 0.35 mm, such as no more than 0.40 mm, such as no more than 0.45mm, such as no more than 0.50 mm, such as no more than 0.55, such as nomore than 0.60 mm, such as no more than 0.65 mm, such as no more than0.70 mm, such as preferably no more than 0.75 mm, such as no more than0.80 mm, such as no more than 0.85 mm, such as no more than 0.90 mm,such as no more than 0.95 mm and such as no more than 1.00 mm. Using agap size between the rollers of about 0.45-0.75 mm is preferred, such asabout 0.45-0.70 mm, such as about 0.45-0.65 mm, such as about 0.45-0.60mm, such as about 0.45-0.55 mm, such as about 0.45-0.50 mm, such asabout 0.50-0.75 mm, such as about 0.55-0.75 mm, such as about 0.60-0.75mm, such as about 0.65-0.75 mm, such as about 0.70-0.75 mm, such asabout 0.50-0.70 mm, such as about 0.50-0.65 mm, such as about 0.50-0.60mm, such as about 0.60-0.70 mm, such as about 0.60-0.65 mm. A gap sizeof about 0.40 mm results in a harsh/strong compression, whereas a gapsize of about 0.75 mm results in a gentle compression.

Preferably, the rollers performing said roller compaction have adiameter of about 100 mm, such as about 80 mm, such as about 70 mm, suchas about 38-62 mm, such as about 43-57 mm, such as preferably about48-52 mm. Said rollers are preferably made out of an inflexible andinert material which does not transfer roller material to saidcompressed collagen carriers upon compaction, i.e. the surface of therollers are important. In an embodiment, the rollers are polished.

In one embodiment, the term “rolled collagen carrier” preferably is arolled collagen carrier characterized by the following physicalproperties: a coating comprising solid fibrinogen and solid thrombinthat is evenly distributed and fixed upon said collagen carrier, andhaving at least one of the following physical properties:

-   -   I. a diameter of at the most 10 mm    -   II. a sterility assurance level (SAL) of 10⁻⁶.

For example, the rolled collagen carrier can have a diameter of at themost 12 mm, such as at the most 11 mm, such as at the most 10 mm, forexample at the most 8 mm, such as at the most 6 mm, for example at themost 4 mm and optionally a sterility assurance level (SAL) of 10⁻⁶.

It should be noted that the rolled collagen carrier may optionally havebeen humidified prior to becoming rolled to at least one side of saidcollagen carrier (i.e. the carrier has been rolled after beinghumidified on at least one side), preferably to the front sidecomprising said coating resulting in a rolled collagen carrier havingthe coating externally oriented. Said rolled collagen carrier hasoptionally been at least partly mechanically processed, optionally alsoat least partly mechanically humidified.

By the term “rolled compressed collagen carrier” is meant a rolledcompressed collagen carrier characterized by the following physicalproperties: a coating comprising solid fibrinogen and solid thrombinthat is evenly distributed and fixed upon said collagen carrier, andhaving at least one of the following physical properties:

-   -   I. a diameter of at the most 10 mm    -   II. a sterility assurance level (SAL) of 10⁻⁶.

It should be noted that said rolled compressed collagen carrier mayoptionally have been humidified prior to becoming compressed and/oroptionally at least partly mechanically rolled.

Thus, an advantage of the invention is that said rolled compressedcollagen carrier is ready to use in minimally invasive surgery, such asready to be inserted into endoscopic devices. Thus, it is preferred thatthe rolled compressed collagen carrier has a diameter smaller than 14mm, such as smaller than 12 mm, smaller than 10 mm, such as smaller than9, preferably smaller than 8, such as smaller than 7 mm

By the term “mechanically rolled compressed collagen carrier” is meant acollagen carrier that has been mechanically compressed and thereaftermechanically rolled and which is characterized by the following physicalproperties: a coating comprising solid fibrinogen and solid thrombinthat is evenly distributed and fixed upon said mechanically rolledcompressed collagen carrier, and having at least one of the followingphysical properties:

-   -   I. a diameter of at the most 10 mm    -   II. a sterility assurance level (SAL) of 10⁻⁶.

Optionally, said mechanically rolled compressed collagen carrier hasbeen mechanically humidified during processing.

By the term “humidifying or humidification” is meant the process ofhumidifying/moisturizing at least part of a collagen carrier with atleast one liquid solvent to preferably at least one side of said carrierwhich has at least one side coated with a coating comprisingbiologically active substances. If more than one side of the carrier iscoated with a coating comprising biologically active substances, thenthe term may comprise humidifying such as at least two sides, such as atleast three sides, such as at least four sides, such as at least fivesides, such as all sides of said collagen carrier. The humidified sideis preferably the side comprising a coating, but it may also be a sidethat does not comprise a coating. Humidifying as used in e.g.humidifying at least a part of said collagen carrier is preferably alsoused to mean the step of applying a liquid substance to a collagencarrier.

A device for applying moisture is used to characterise a device thathumidifies at least a part of a collagen carrier. It is noted thatmoisture is used in a broad context and is not limited to water vapouror water in general. In particular, the solvent applied is preferably asolvent not being water or contains less than 2.4% w/w, such as lessthan 1% w/w, such as less than 0.5 w/w % of water, as disclosed belowwith respect to preferred solvents.

Thus, the term “humidified collagen carrier” is meant to mean a collagencarrier that has been exposed to at least one liquid solvent topreferably at least one side of said carrier, such as at least twosides, such as at least three sides, such as at least four sides, suchas at least five sides, such as all sides, to achieve a humidifiedcollagen carrier.

In one embodiment of the present invention the collagen carrier ispreferably humidified on at least one side of said carrier (i.e. thefront) which has at least one side coated with a coating comprisingbiologically active substances before being compressed and/or beforebeing rolled. The words humidified and moisturized are usedinterchangeably. In another embodiment it is preferred to humidify boththe front and back of a collagen carrier of the present invention,wherein the front comprises said coating. Said humidified collagencarrier has optionally been at least partly mechanically processed.

In an embodiment of the present invention said humidified collagencarrier has a coating comprising solid fibrinogen and solid thrombinthat is evenly distributed and fixed upon said collagen carrier, andhaving at least one of the following physical properties:

-   -   I. a diameter of at the most 10 mm    -   II. a sterility assurance level (SAL) of 10⁻⁶.

By the term “solvent” is meant any suitable solvent such asphysiological saline, purified water, aqueous vapour or any suitableorganic solvent such as ethanol, dehydrated ethanol with a maximumcontent of 0.1% water, isopropanol or methanol. An alcohol is selectedfrom the group consisting of ethanol, dehydrated ethanol with a maximumcontent of 0.1% water, 1-propanol, 2-propanol, 2-methyl-2-propanol,ethylene glycol, 1-butanol, 2-butanol or any combination thereof. In anembodiment a solvent is selected from ethanol, dehydrated ethanol with amaximum content of 0.1% water, isopropanol, 1-propanol,2-methyl-2-propanol, water or any combination thereof. In a furtherembodiment, a solvent is selected from ethanol, dehydrated ethanol witha maximum content of 0.1% water, isopropanol, water or combinationsthereof. In a embodiment the ethanol is dehydrated ethanol with amaximum content of 0.1% water. In one embodiment of the applied solvent,the amount of applied solvent is about 0.8-10.75 mg/cm² collagencarrier, such as about 1.2-10.75 mg/cm² collagen carrier, such as about0.8-10.4 mg/cm² collagen carrier, such as about 0.8-6.1 mg/cm² collagencarrier, such as about 1.2-4.7 mg/cm² collagen carrier, such as about2.85-4.24 mg/cm². An alcohol—preferably ethanol—is a preferred solvent.In an embodiment, the solvent essentially consist of a mixture ofethanol or dehydrated ethanol with a maximum content of 0.1% water andwater or isopropanol and water, wherein the amount of water is up to20%, such as up to 18%, such as up to 16%, such as up to 14%, such as upto 12%, such as up to 10%, such as up to 8%, such as up to 6%, such asup to 5%, such as up to 4%, such as up to 3%, such as 2.4%, such as upto 2%, such as up to 1.5%, such as up to 1%, such as up to 0.5%. Thesolvent may also contain fibrinogen and/or thrombin and/or albuminand/or some salt. In a further embodiment, ethanol or dehydrated ethanolwith a maximum content of 0.1% water is the preferred solvent and isused in an amount of about 9 mg ethanol/cm² collagen carrier, such asabout 8 mg ethanol/cm² collagen carrier, such as about 7 mg ethanol/cm²collagen carrier, such as about 6 mg ethanol/cm² collagen carrier, suchas about 5 mg ethanol/cm² collagen carrier, such as about 4 mgethanol/cm² collagen carrier, such as about 3 mg ethanol/cm² collagencarrier, such as about 2 mg ethanol/cm² collagen carrier, such as about1.2 mg ethanol/cm² collagen carrier, such as about 1 mg ethanol/cm²collagen carrier, such as about 0.5 mg ethanol/cm² collagen carrier.

Without being bound by theory, it is speculated that using more thanabout 10.75 mg ethanol or dehydrated ethanol with a maximum content of0.1% water/cm² collagen carrier, such as about 10.4, mg ethanol/cm²collagen carrier could make said collagen carriers become sticky whenbeing compressed. Hence, using an ethanol level of no more than 10.75 mgethanol/cm² collagen fleece is preferred.

By the term “relative humidity (RH)” is meant the amount of water vaporin a mixture of air and water vapor.

In an embodiment, the process according to the present invention isperformed at 10-75% RH, such as 30-50% RH, such as 30-60%, such as30-64% RH, such as 30-65% RH, such as 30-70% RH, such as 40-60% RH, suchas 40-64% RH, such as 40-70% RH and optionally at a temperature of 5-30°C., such as 18-22° C., such as 18-25° C. In a preferred embodiment, RHis 30-50% and the temperature is 18-22° C. which is the preferredrelative humidity range and temperature range of the room (e.g.manufacturing facility) where the rolled and/or compressed collagencarriers are processed. See further below when the term “drying” isdefined. In another embodiment the relative humidity range andtemperature of the room (e.g. manufacturing facility) where the rolledand/or compressed collagen carriers are processed is about 25° C. and64-70% RH.

By the term “density” or the mass density of a material is meant thematerial's mass per unit volume. The symbol most often used for densityis p but in the present context, density is defined as weight per unitvolume mg/cm³, which is also called specific weight. The method and theequipment used for determining the density are disclosed in furtherdetail in the example section below. The density of a collagen carrieraccording to the present invention is the density of the collagencarrier excluding the coating layer. In an embodiment of the presentinvention, the density of the collagen carrier before humidificationand/or rolling and/or compression, such as for the collagen carrierprovided in step (a) of the present invention, is in the range of 1-10mg/cm³, such as in the range of 1-9 mg/cm³, such as in the range of 1-8mg/cm³, such as in the range of 1-7 mg/cm³, such as in the range of 1-6mg/cm³, such as in the range of 1-5 mg/cm³, such as in the range of 1-4mg/cm³, such as in the range of 1-3 mg/cm³, such as in the range of 1-2mg/cm³, such as in the range of 2-9 mg/cm³, such as in the range of 2-8mg/cm³, such as in the range of 2-7 mg/cm³, such as in the range of 2-6mg/cm³, such as in the range of 2-5 mg/cm³, such as in the range of 2-4mg/cm³, such as in the range of 3-9 mg/cm³, such as in the range of 3-8mg/cm³, such as in the range of 3-7 mg/cm³, such as in the range of 3-6mg/cm³, such as in the range of 3-5 mg/cm³, preferably such as in therange of 3.0-4.5 mg/cm³, such as in the range of 3.0-4.4 mg/cm³, such asin the range of 3.0-4.3 mg/cm³, such as in the range of 3.0-4.2 mg/cm³,such as in the range of 3.0-4.1 mg/cm³, such as in the range of 3.0-4.0mg/cm³, such as in the range of 3.0-3.9 mg/cm³, such as in the range of3.0-3.8 mg/cm³, such as in the range of 3.0-3.7 mg/cm³, such as in therange of 3.0-3.6 mg/cm³, such as in the range of 3.0-3.5 mg/cm³, such asin the range of 3.0-3.4 mg/cm³, such as in the range of 3.0-3.3 mg/cm³,such as in the range of 3.0-3.2 mg/cm³, such as in the range of 3.0-3.1mg/cm³, such as in the range of 3.1-4.5 mg/cm³, such as in the range of3.2-4.5 mg/cm³, such as in the range of 3.3-4.5 mg/cm³, such as in therange of 3.4-4.5 mg/cm³, such as in the range of 3.5-4.5 mg/cm³, such asin the range of 3.6-4.5 mg/cm³, such as in the range of 3.7-4.5 mg/cm³,such as in the range of 3.8-4.5 mg/cm³, such as in the range of 3.9-4.5mg/cm³, such as in the range of 4.0-4.5 mg/cm³, such as in the range of4.1-4.5 mg/cm³, such as in the range of 4.2-4.5 mg/cm³, such as in therange of 4.3-4.5 mg/cm³, such as in the range of 4.4-4.5 mg/cm³.

The density of a humidified and/or compressed and/or rolled collagencarrier of the present invention is preferably in the range of 1-15mg/cm³, such as in the range of 2-15 mg/cm³, such as in the range of3-15 mg/cm³, such as in the range of 4-15 mg/cm³, such as in the rangeof 5-15 mg/cm³, such as in the range of 6-15 mg/cm³, such as in therange of 7-15 mg/cm³, such as in the range of 8-15 mg/cm³, such as inthe range of 9-15 mg/cm³, such as in the range of 10-15 mg/cm³, such asin the range of 11-15 mg/cm³, such as in the range of 12-15 mg/cm³, suchas in the range of 13-15 mg/cm³, such as in the range of 14-15 mg/cm³,such as in the range of 3-14 mg/cm³, such as in the range of 3-12mg/cm³, such as in the range of 3-10 mg/cm³, such as in the range of 3-9mg/cm³, such as in the range of 3-8 mg/cm³, such as in the range of 3-7mg/cm³, such as in the range of 3-6 mg/cm³, such as in the range of 3-5mg/cm³, such as in the range of 3.0-4.5 mg/cm³, such as in the range of3.0-4.4 mg/cm³, such as in the range of 3.0-4.3 mg/cm³, such as in therange of 3.0-4.2 mg/cm³, such as in the range of 3.0-4.1 mg/cm³, such asin the range of 3.0-4.0 mg/cm³, such as in the range of 3.0-3.9 mg/cm³,such as in the range of 3.0-3.8 mg/cm³, such as in the range of 3.0-3.7mg/cm³, such as in the range of 3.0-3.6 mg/cm³, such as in the range of3.0-3.5 mg/cm³, such as in the range of 3.0-3.4 mg/cm³, such as in therange of 3.0-3.3 mg/cm³, such as in the range of 3.0-3.2 mg/cm³, such asin the range of 3.0-3.1 mg/cm³, such as in the range of 3.1-4.5 mg/cm³,such as in the range of 3.2-4.5 mg/cm³, such as in the range of 3.3-4.5mg/cm³, such as in the range of 3.4-4.5 mg/cm³, such as in the range of3.5-4.5 mg/cm³, such as in the range of 3.6-4.5 mg/cm³, such as in therange of 3.7-4.5 mg/cm³, such as in the range of 3.8-4.5 mg/cm³, such asin the range of 3.9-4.5 mg/cm³, such as in the range of 4.0-4.5 mg/cm³,such as in the range of 4.1-4.5 mg/cm³, such as in the range of 4.2-4.5mg/cm³, such as in the range of 4.3-4.5 mg/cm³, such as in the range of4.4-4.5 mg/cm³.

The density of a humidified and/or compressed and rolled collagencarrier of the present invention is measured upon unrolling said rolledcollagen carrier of the present invention. Please note that the densityof a collagen carrier of the present invention is the density of thecollagen carrier excluding the coating layer.

It is presently preferred to determine the density by weighing acollagen carrier of known volume, such as a rolled and/or compressedcollagen carrier of a certain size (see the examples section), such as alarge size collagen carrier (also called a strip or a fleece). Thedensity is calculated by dividing the mass of the collagen carrier bythe volume of the collagen carrier. The method and the equipment usedfor determining the density are disclosed in further detail in theexample section below.

By the term “coating” is preferably meant a coating either comprising oressentially consisting of the biologically active substances fibrinogenand thrombin that are evenly distributed and fixed upon at least oneside of a collagen carrier of the present invention, such as a rolledand/or compressed collagen carrier, such as an unrolled rolled and/orcompressed collagen carrier. The coating may also include e.g.riboflavin (yellow color as marker of coated area). In one embodiment ofthe present invention, the active substances are preferably solid humanfibrinogen, solid human thrombin and optionally solid riboflavin. Thusin one embodiment of the invention, the coating essentially consists ofsolid human fibrinogen, solid human thrombin and solid riboflavin. Thecoating is present on at least one side of the collagen carrier, such asa rolled and/or compressed collagen carrier, such as an unrolled rolledand/or compressed collagen carrier. Hence, in one embodiment thecollagen carrier, such as a rolled and/or compressed collagen carrier,such as an unrolled rolled and/or compressed collagen carrier comprisesone or more active sides wherein fibrinogen is present in an amount of1.3-10 mg/cm², such as 2-10 mg/cm², such as 4.3-6.7 mg/cm², preferablyabout 3.6-7.4 mg/cm², such as about 5.5 mg/cm², and thrombin is presentin an amount of 0.9-20 IU/cm², such as 0.9-15 IU/cm², such as 0.9-10IU/cm², such as 1.0-5.5 IU/cm², preferably such as about 1.3-2.7 IU/cm²,such as about 2.0 IU/cm². Said coating is preferably applied to at leastone side of said collagen carrier, such as a rolled and/or compressedcollagen carrier, such as an unrolled rolled and/or compressed collagencarrier.

When the collagen carrier, such as a rolled and/or compressed collagencarrier, such as an unrolled rolled and/or compressed collagen carrier,has a coating on one side of said carrier and when it is rolled the sidecoated with the biologically active substances can be externallyoriented on said rolled collagen carrier, or the side coated with thebiologically active substances can be internally oriented on the rolledcollagen carrier. Presently, the first alternative is preferred for arolled compressed collagen carrier of the present invention, i.e.external orientation of said coating.

By the term “diameter” of e.g. the rolled collagen carrier is meant thediameter of the cross section of any type of collagen carrier that hasbeen rolled or coiled according to the present invention. Thus, thediameter of the resulting rolled collagen carrier as measured on thecross section (e.g. the shortest side) is about 5-12 mm, such as about6-11, such as about 7-10 mm, such as about 8-9 mm, such as at the most11 mm, preferably such as at the most 10 mm, preferably such as at themost 9 mm, such as at the most 8 mm, such as at the most 7 mm, such asat the most 6 mm, such as at the most 5 mm, such as at the most 4.5 mm,such as at the most 4 mm, such as at the most 3.5 mm, such as at themost 3 mm, such as at the most 2.5 mm, such as at the most 2.0 mm, suchas at the most 1.5 mm, such as at the most 1.0 mm. The preferreddiameter is less than 10 mm for midi sized fleeces, i.e. midi sizedfleeces have the dimensions 46-49 mm*46-50 mm*4-7 mm.

By the term “thickness” is meant the shortest measurable distance acrossany collagen carrier of the invention that is unrolled or nonrolled,which means that the thickness depends on whether the collagen carrierhas been previously rolled or not and/or whether it has been previouslycompressed, humidified or not. When the term thickness is used todescribe any type of unrolled or nonrolled collagen carrier according tothe present invention the thickness is meant to mean the thickness whichis about 1-10 mm, such as about 2-8, such as about 4-6, such as at themost 10 mm, such as at the most 9 mm, such as at the most 8 mm, such asat the most 7 mm, such as at the most 6 mm, such as at the most 5 mm,such as at the most 4 mm, such as at the most 3 mm, such as at the most2 mm, such as at the most 1 mm. In an embodiment the preferred thicknessof a collagen carrier is 4-7 mm. In another embodiment, the preferredthickness of an unrolled collagen carrier is at the most 4 mm.

By the term “sterility assurance level (SAL)” is meant a term used inmicrobiology to describe the probability of a single unit beingnon-sterile after it has been subjected to a sterilization process. Forexample, medical device manufacturers design their sterilizationprocesses for an extremely low SAL leading to a 10⁻⁶ microbial survivorprobability, i.e. assurance of less than or equal to 1 chance in 1million that viable microorganisms are present in the sterilized device,as defined in USP 34<1211> (United States Pharmacopeia version 32,chapter 1211. SAL is also used to describe the killing efficacy of asterilization process, where a very effective sterilization process hasa very low SAL.

Sterilisation can occur before and/or after any packaging steps.

Gamma radiation can be used as a sterilization method to kill livingorganisms in a process called irradiation. Applications of irradiationinclude sterilizing medical equipment as an alternative to autoclaves orchemical means. In one embodiment of the present invention, a collagencarrier, such as a rolled and/or compressed collagen carrier, issubjected to gamma radiation. The gamma radiation may reduce theadhesion of the collagen carrier, such as no more than 0.5%, such as nomore than 1%, such as no more than 2%, such as no more than 3%, such asno more than 4%, such as no more than 5%, such as no more than 6%, suchas no more than 7%, such as no more than 8%, such as no more than 9%,such as preferably no more than 10%, such as no more than 11%, such asno more than 12%, such as no more than 13%, such as no more than 14%,such as no more than 15%, such as no more than 16%, such as no more than17%, such as no more than 18%, such as no more than 19%, such as no morethan 20%, such as no more than 25%. This was evaluated in vitro byvisual inspection of adherence of a rolled collagen carrier according tothe invention on liver tissue. Fibrinogen is preferably present in anamount of 2-10 mg/cm² and thrombin is preferably present in an amount of1.0-5.5 IU/cm² after the irradiation process and it is preferred thatthe levels may exceed their respective levels such as no more than 0.5%,such as no more than 1%, such as no more than 2%, such as no more than3%, such as no more than 4%, such as no more than 5%, such as no morethan 6%, such as no more than 7%, such as no more than 8%, such as nomore than 9%, such as preferably no more than 10%, such as no more than11%, such as no more than 12%, such as no more than 13%, such as no morethan 14%, such as no more than 15%, such as no more than 16%, such as nomore than 17%, such as no more than 18%, such as no more than 19%, suchas no more than 20%, such as no more than 25%. It is noted that“exceeding their respective levels” means that the values may eitherincrease or decrease.

It is preferred that the rolled and/or compressed collagen carrier canbe stored for an acceptable duration of time whilst maintaining theirbiological and physiochemical properties, i.e. preferably, storageneither affects the physical and chemical properties of said rolledand/or compressed collagen carrier nor the in vitro adherence (to livertissue) of the rolled and/or compressed collagen carriers. An acceptableshelf-life is preferably up to 60 months, such as up to 54 months, suchas up to 48 months, such as up to 42 months, such as up to 36 months,such as up to 30 months, such as up to 24 months, such as up to 18months, such as up to 12 months, such as up to 6 months, such as up to 5months, such as up to 4 months, such as up to 3 months, such as up to 2months, such as up to 1 month. Hence, it is preferred that rolled and/orcompressed collagen carriers of the present invention are stable.

By the word “stable” is meant that said rolled and/or compressedcollagen carriers are physiochemical and biologically stable meaningthat they retain the same properties as they had when they wereprepared. Hence, said rolled and/or compressed collagen carriers retaintheir stability under transport, warehousing (storage), logistics,sales, and up to and including the end use of said rolled and/orcompressed collagen carriers i.e. the collagen carriers maintainregulations and all end-use requirements.

By the term “drying” is meant any well known method of drying an objectsuch as by passive evaporation, desiccation, blowing air with a humiditylower than the object that needs drying over said object, applying heatetc. In one embodiment drying is performed in a drying tunnel i.e.tunnel comprises a conveyor belt transporting the trays that containsthe rolled collagen carriers through the tunnel with an airflow securingthe drying. In one embodiment the passage through the tunnel, i.e. thelength of the drying takes around 30 min. In another embodiment thedrying tunnel dries off the solvent such as dries off ethanol, e.g.dries off isopropanol, e.g. dries off isopropanol and ethanol. Water isdried off using a desiccant, such as e.g. silica gel. The drying off ofwater may take up to about 48 hours, such as up to about 36 hours, suchas up to about 24 hrs, such as up to about 18 hours, such as up to about12 hours, such as up to about 6 hours, such as up to about 2 hours. Thedrying off of water preferably takes up to about 24 hours.

Silica gel is preferably used to mean a granular, vitreous, porous formof silicon dioxide made synthetically from sodium silicate. Silica gelis a commonly used desiccant as beads packed in a permeable bag.

Endoscopic instrument: by “endoscopic instrument” is meant herein anyendoscopic instrument known to one skilled in the art, for exampleendoscopic grab tongs, endoscopic pincet, endoscopic dissector,endoscopic forceps, Johansons clamp or other endoscopic clamp,endoscopic scissors, an endoscopic grasper, two or more graspers,laparoscopic swabs (preferably fastened to long pins or fixed tograspers), or another suitable endoscopic instrument.

In one embodiment of the present invention, the drying of an optionallyhumidified rolled and/or compressed collagen carrier according to theinvention neither affects the physical and chemical properties of saidcollagen carrier nor the in vitro adherence (to liver tissue) of saidcollagen carrier. In one embodiment of the present invention, anoptionally humidified rolled and/or compressed collagen carrier is driedby passive evaporation of a solvent, preferably ethanol, by controllingthe room temperature and room humidity to within the ranges of which is3-35° C., 5-80% RH, such as 13-35° C., 36-65% RH, such as 23-35° C.,36-65% RH, such as 33-35° C., 36-65% RH, such as 3-25° C., 36-65% RH,such as 3-15° C., 36-65% RH, such as 3-5° C., 36-65% RH, preferably18-22° C., 40-60% RH, such as 18-22° C., 36-65% RH, such as at 20-25°C., 40-60% RH, such as at 22-25° C., 40-60% RH, such as at 24-25° C.,40-60% RH, such as at 18-23° C., 40-60% RH, such as at 18-21° C., 40-60%RH, such as at 18-19° C., 40-60% RH, such as at 18-25° C., 35-60% RH,such as at 18-25° C., 30-60% RH, such as at 18-25° C., 40-65% RH, suchas at 18-25° C., 40-70% RH, such as at 18-25° C., 40-75% RH, such as at18-25° C., 40-80% RH, such as at 18-25° C., 45-80% RH, such as at 18-25°C., 50-80% RH, such as at 18-25° C., 55-80% RH, such as at 18-25° C.,60-80% RH, such as at 18-25° C., 65-80% RH, such as at 18-25° C., 70-80%RH, such as at 18-25° C., 75-80% RH. Said optionally humidified rolledand/or compressed collagen carrier is preferably dried 30 minutes byblowing air with a humidity lower than said collagen carrier (such as arolled and/or compressed collagen carrier that needs drying) over saidcollagen carrier followed by passive evaporation of the solvent byplacing said collagen carrier in a desiccator.

After the coiled collagen carriers has been dried in e.g. the dryingtunnel for preferably about 30 minutes, the coiled collagen carriers maybe further dried e.g. by arranging the coiled collagen carriers in asealed box together with a desiccant. The coiled collagen carriers arepreferably present in the sealed box for up to 72 hours.

A drying time of up to 72 hours, such as up to 48 hours, preferably upto 24 hours is preferred, such as up to 20 hours, such as up to 15hours, such as up to 10 hours, such as up to 5 hours, such as up to 1hour, such as up to 50 minutes, such as up to 40 minutes, preferablysuch as up to 30 minutes, such as up to 20 minutes, such as up to 10minutes, such as up to 5 minutes, such as up to 1 minute, such as up to50 seconds, such as up to 40 seconds, such as up to 30 seconds, such asup to 20 seconds, such as up to 10 seconds, such as up to 5 seconds.

A residual amount of the applied at least one liquid solvent to thecollagen carrier, such as a rolled and/or compressed collagen carrier isacceptable such as no more than 0.1% w/w, or such as no more than 0.2%w/w, or such as no more than 0.5% w/w, or such as no more than 0.8% w/wor such as no more than 1.0% w/w, or such as no more than 1.2% w/w, orsuch as no more than 1.4% w/w, or preferably such as no more than 1.6%w/w, or such as no more than 1.8% w/w, or such as no more than 2.0% w/w,or such as no more than 2.5% w/w, or such as no more than 3.0% w/w, orsuch as no more than 3.5% w/w, or such as no more than 4.0% w/w, or suchas no more than 5.0% w/w, or such as no more than 8.0% w/w, or such asno more than 10.0% w/w, or such as no more than 12.5% w/w, or such as nomore than 15.0% w/w, or such as no more than 17.5% w/w, or such as nomore than 20.0% w/w, or such as no more than 22.5% w/w, or such as nomore than 25.0% w/w, or such as no more than 27.5% w/w, or such as nomore than 30.0% w/w, or such as no more than 32.5% w/w, or such as nomore than 35.0% w/w. When the applied liquid solvent is ethanol, no morethan 1.6% w/w residual ethanol is preferred and/or when the appliedliquid solvent is water no more than 8.0% w/w residual water ispreferred, preferably such as no more than 5.0% w/w. A residual amountof the applied at least one liquid solvent, such as at least two liquidsolvents, such as at least three liquid solvents to the collagencarrier, such as a rolled and/or compressed collagen carrier isacceptable.

It may happen that one or more solvents or moisture from the room(aqueous vapour) is absorbed passively by a collagen carrier, such as arolled and/or compressed collagen carrier during processing. In oneembodiments, if such passive absorption of moisture, such as water, hastaken place a residual amount of said moisture is acceptable such as nomore than 0.1% w/w, such as no more than 0.2% w/w, such as no more than0.5% w/w, such as no more than 0.8% w/w such as no more than 1.0% w/w,such as no more than 1.2% w/w, such as no more than 1.4% w/w, such as nomore than 1.6% w/w, such as no more than 1.8% w/w, such as no more than2.0% w/w, such as no more than 2.5% w/w, such as no more than 3.0% w/w,such as no more than 3.5% w/w, such as no more than 4.0% w/w, preferablysuch as no more than 5.0% w/w, such as no more than 8.0% w/w, such as nomore than 10.0% w/w, such as no more than 12.5% w/w, such as no morethan 15.0% w/w, such as no more than 17.5% w/w, such as no more than20.0% w/w, such as no more than 22.5% w/w, such as no more than 25.0%w/w, such as no more than 27.5% w/w, such as no more than 30.0% w/w,such as no more than 32.5% w/w, such as no more than 35.0% w/w. When thepassively absorbed solvent is water no more than 8.0% w/w residual wateris preferred, preferably such as no more than 5.0% w/w. Residual solventis measured by conventional methods known to the person skilled in theart, such as by using gas chromatography (GC). GC is a common type ofchromatography used in analytical chemistry for separating and analyzingcompounds that can be vaporized without decomposition. In the presentinvention, GC is used to determine one or more solvents or moisture fromthe room (aqueous vapour) in the collagen carrier.

By the term “sterilizing” is meant any well-known method of sterilizingan object such as in the present invention a collagen carrier, such as arolled and/or compressed collagen carrier. Any such appropriatesterilization method should result in the required probability of asingle unit being non-sterile after it has been subjected to thesterilization process. Hence, preferably not more than one collagencarrier, such as a rolled and/or compressed collagen carrier in amillion should be nonsterile after the sterilization process. An exampleof a sterilization process is gamma radiation. Sterilization can also beachieved by applying the proper combinations of heat, chemicals,irradiation, and high pressure, but these are less preferred methods. Ina preferred embodiment the sterilization is performed using gammairradiation.

By the term “packing” is meant any well-known method of packaging anobject such as in the present invention a collagen carrier, such as arolled and/or compressed collagen carrier. Packaging and packing arewords that are used interchangeably within this context. Packaging ismeant to mean a coordinated system of preparing goods for transport,warehousing, logistics, sales, and end use. Packaging can for examplecontain, protect, preserve, transport, inform, and sell an object,preferably such an object as the collagen carrier, such as a rolledand/or compressed collagen carrier of the present invention. A suitablecontainer is used for packing the collagen carrier, such as a rolledand/or compressed collagen carrier of the present invention.

By the term “suitable container” is meant in one embodiment anycontainer that is suitable for transport, warehousing (storage),logistics, sales, and for the end use of a collagen carrier, such as arolled and/or compressed collagen carrier of the present invention.Hence, said suitable container encloses and/or protects said collagencarrier. Thus preferably said collagen carrier, such as a rolled and/orcompressed collagen carrier retains its properties substantially as theywere at the time of packaging. An example of a suitable container is atray made of PET (polyethylene terephthalate) or polystyrene shaped tofit the rolled collagen carrier of the present invention. A suitablecontainer according to the present invention is further sealed with alid, such as e.g. a Tyvec lid. In an embodiment of the invention, theclosed tray with a lid is further placed inside a double aluminium foil,preferably with a desiccant. In an even further embodiment of theinvention, the double aluminium foil is marked to indicate that thecontent has been sterilized (see further below). Other suitablecontainers are well known in the art.

In an embodiment package testing is conducted and documented to ensurethat packages meet regulations and all end-use requirements.Manufacturing processes are controlled and validated to ensureconsistent performance.

Preferably, a suitable container of the present invention is sterilizedin the package. Medical device packaging is highly regulated and thesterility must be maintained throughout distribution to allow immediateuse by physicians. A series of special packaging tests is well known inthe art and used to measure the ability of the package to maintainsterility. Relevant standards include: ASTM D1585 —Guide for IntegrityTesting of Porous Medical Packages, ASTM F2097—Standard Guide for Designand Evaluation of Primary Flexible Packaging for Medical Products, EN868 Packaging materials and systems for medical devices which are to besterilized. General requirements and test methods, ISO 11607 Packagingfor terminally sterilized medical devices, and others.

In an embodiment the container is a foil packaging material, such as asingle or double aluminium foil or a plastic packaging material, such asa polystyrene or PET (polyethylene terephthalate) or a combination of afoil and plastic packaging material, such as a single or doublealuminium foil and as a polystyrene or PET (polyethylene terephthalate).

By the term “weight-weight percentage” or “% w/w” is meant gramssubstance per grams of another substance in percent (per 100 gram).Thus, if e.g. residual water is present in an amount of 2% w/w in acollagen carrier, it is meant to mean 2 grams of water is present with98 grams of collagen carrier. The total weight will be 100 grams of thecollagen carrier including the residual water but the volume of the 100grams of residual may be different from 100 ml.

Note that by the “weight” of the collagen carriers is meant the weightof the collagen carrier excluding the weight of the coating layer.

It should be noted that embodiments and features described in thecontext of one of the aspects of the present invention also apply to theother aspects of the invention i.e. all aspects relating to a rolledcompressed collagen carrier also apply to a compressed collagen carrieror a rolled collagen carrier or an unrolled rolled compressed collagencarrier or a coiled collagen carrier (as the terms “coiled” and “rolled”are used interchangeably herein), and similarly for the process aspects.

An aspect of the present invention relates to a process for coiling acollagen carrier, the collagen carrier comprising (i) a collagen layerand (ii) a coating layer comprising fibrinogen and thrombin, saidprocess comprising the sequential steps of:

-   -   humidifying at least part of said collagen carrier,    -   coiling said collagen carrier by gripping the collagen carrier        between a pair of elongated members, and rotating the pair of        elongated members about an axis being parallel to a longitudinal        extension of the elongate members in order to coil the collagen        carrier on the members, while the collagen carrier is supported        by a support device,    -   drying the coiled collagen carrier,        thereby providing a form-stable coiled collagen carrier.

Another aspect of the present invention relates to a process for coilinga collagen carrier, the collagen carrier comprising (i) a collagen layerand (ii) a coating layer preferably comprising fibrinogen and thrombin,said process comprising the sequential steps of:

-   -   humidifying at least part of said collagen carrier,    -   coiling said collagen carrier    -   drying the coiled collagen carrier,        thereby providing a form-stable coiled collagen carrier.

Any type of fibrinogen and/or thrombin can be used in the coating layer,preferably the fibrinogen and/or thrombin used in the coating layer ismostly solid and/or solid. It is preferred that the fibrinogen and/orthrombin are dry.

Preferably, said sequential steps are consecutive steps. In anembodiment of the present invention, the process consists of theabove-mentioned process steps. In another embodiment, the processcomprises or consists of the above-mentioned process steps and a furtherpacking step wherein the coiled product is sealed in a container, andsterilized. In an embodiment of the present invention, the coiling isperformed by gripping the collagen carrier using at least one grippingdevice. In an embodiment of the present invention, the coiling isperformed by gripping the collagen carrier using at least one pair oftweezers or pincers.

The drying of the coiled collagen carrier can be done using any suitabledrying process, such as e.g. by blowing air with a humidity lower thanthe coiled collagen carrier and optionally applying heat to the air.Preferably, said drying is at least 5 minutes long, such as between 5minutes and 1 hour, such as between 20 minutes and 40 minutes long, suchas between 25 and 35 minutes long. A ventilation tunnel can for examplebe used for the drying step.

Any surface of the collagen carrier can be humidified. Preferably, atleast the coating layer of said collagen carrier is humidified. In oneembodiment of the present invention only the coating layer ishumidified, in another embodiment of the invention both the top andbottom sides of the collagen carrier are humidified. In anotherembodiment of the present invention, the surface humidified is thecollagen layer.

Preferably, the collagen carrier is humidified by a solvent. Anysuitable solvent can be used, such as an organic solvent or water. In anembodiment of the present invention, the solvent comprises or consistsof ethanol, such as dehydrated ethanol with a maximum content of 0.1%water. In another embodiment, the solvent comprises or consists ofethanol, such as dehydrated ethanol with a maximum content of 0.1%water, and water. The solvent can also comprise or consist ofisopropanol. The solvent can alternatively be a mixture of at least 70%ethanol such as dehydrated ethanol with a maximum content of 0.1% waterand another solvent (such as water), such as at least 80% ethanol, suchas at least 90% ethanol, such as at least 95% ethanol. The solvent canin another embodiment be a mixture of at least 80% isopropanol andanother solvent (such as water), such as at least 90% or 95%isopropanol. The solvent can also comprise fibrinogen and/or thrombinand/or other factors. In a preferred embodiment the ethanol may bedehydrated ethanol with a maximum content of 0.1% water.

In an embodiment of the present invention, the rolling/coiling up stepis performed after the coating layer has been softened.

Preferably, the coating layer of the collagen carrier is humidifiedusing a solvent. In an embodiment of the present invention, the collagencarrier is humidified on the coating layer by a solvent in an amountbetween 0.1 and 25 cm² surface of the coating layer, such as e.g.1.2-10.75 mg/cm² surface of the coating layer. For rolled versions ofthe standard TachoSil® sizes available on the market (such as e.g. midisized fleeces), the following solvent amounts are preferred on thecoating layer: 30-160 mg solvent (such as ethanol) per collagen carrier,such as 30-100 mg solvent (such as ethanol) per collagen carrier, suchas preferably 90-100 mg solvent (such as ethanol) per collagen carrier,such as for a collagen carrier with a 25 cm² coating surface such as forthe small or midi sized Tachosil® collagen carrier. In an embodiment ofthe present invention, the solvent comprises or consists of ethanol ordehydrated ethanol with a maximum content of 0.1% water.

In an embodiment of the process for coiling a collagen carrier, theprocess further comprises the step of compressing the collagen carrierto reduce the thickness of the collagen carrier. For example, thecollagen carrier can be compressed with a compression ratio between 2and 18, such as e.g. 4-14, such as preferably between 6-12. Thecompression step can in one embodiment be performed by passing thehumidified collagen carrier through a set of rollers having a gap sizebeing smaller than the thickness of the collagen carrier before passingthrough the set of rollers. An example gap size is between 0.2 mm and 2mm, such as e.g. 0.4-1.6 mm, such as between 0.5-1.0 mm, or no more than0.75 mm, such as e.g. 0.5-0.75. One preferred gap size is 0.6 mm. Thecompression is preferably performed prior to the coiling of the collagencarrier.

The compression device may preferably include a certain flexibilityallowing the compression ratio to be influenced by the collagen carrierand rendering the compression device more suited for handling collagencarriers of different densities. In embodiments where the compressiondevice comprises a set of rollers, this is implemented by allowing therollers to move apart each other so that the gap size increases. Themovement of the rollers to increase the gap size is caused by thecollagen carrier pressing on the surface of the rollers during itpassage through the gap. Mechanically this may preferably be implementedby allowing some flexibility in the means used for mounting the rollersor by mounting one or both rollers in a manner allowing displacement ofthe rollers in a direction being perpendicular to the axis of rotationand biasing the rollers towards each other by springs.

During the drying step of the coiling process, the coiled collagencarrier can be supported by a support device, e.g. by contacting thesupport device. For example, at least an edge of the coiled collagencarrier is fixed by the support device relatively to the coiled collagencarrier during drying, i.e. the edge of the coiled collagen carrier ispushed against the support device. The support device can be anysuitable shape, such as e.g. a “U” shape, a rounded shape, a tubularshape or any other shape capable of supporting and maintaining thecoiled shape of the collagen carrier while it is drying, prior to theproduct becoming form-stable in the dry state. In one preferredembodiment, the support device is a cavity shaped as a segment of acylinder having at least one open end, and wherein the curved part ofthe cylinder segment extends at least 180° (see e.g. FIG. 1). In oneembodiment of the present invention, the edge of the coiled collagencarrier is arranged inside the segment of the cylinder and the edgeabuts the inner surface of the cylinder.

Preferably, the process of the present invention further comprises thestep of extracting the elongated members from the coiled collagencarrier. For example, the extraction of the elongated members isperformed before drying of the coiled collagen carrier. The elongatedmembers can be a pair of tweezers, so for example the extraction of theat least one pair of tweezers can be performed before drying of thecoiled collagen carrier. Preferably the elongated members form agripping device.

In an embodiment of the present invention, the process further comprisesthe step of arranging the form-stable coiled collagen carrier in acontainer and subsequently sealing the container. For example, thecoiled carrier can be arranged in an inner container and the innercontainer can be arranged in an outer container, further optionallycomprising the step of arranging a desiccator inside the outer containerprior to sealing of the container.

The process of the present invention preferably comprises the step ofsterilizing the coiled collagen carrier. This can for example be doneusing gamma radiation. One embodiment of the present invention comprisesthe step of sterilizing the coiled collagen carrier to a sterilityassurance level (SAL) of 10⁻⁶ using gamma radiation.

The process of the present invention can comprise a step wherein a labelwith information relating to the product of the present invention, suchas e.g. relating to the sterilization level, is placed on the outside ofthe outer container.

In one embodiment of the present invention, the process for coiling acollagen carrier has the feature that the atmosphere surrounding thecollagen carrier and humidification device while being humidified,compressed and coiled, is maintained at a set temperature and/orhumidity. The temperature and/or humidity can for example be in therange of 10−40° C. and 10-70% RH. Preferably, the temperature is 18-22°C. and the relative humidity is 30-50%.

In an embodiment the temperature is 5-30° C., such as 10-25° C., such as10-30° C., such as 15-30° C. In another embodiment the relative humidityis 2-60% RH, such as 10-55% RH, such as 20-55% RH, such as 30-55% RH,such as 40-55% RH. Preferably the relative humidity is 30-50% RH.

According to a broad aspect of the invention, the result of theutilising the apparatus according to the present invention and theprocess according in their broadest aspects to the present invention iscoiled collagen carrier with a number of windings, which coiled collagencarrier after being dried becomes form-stable. In the following, furthercharacteristics of such a coiled collagen carrier are presented.

The windings being referred to as the outer windings are preferably eachwinding of the coiled collagen carrier except the inner most windingwhich typically is coiled to define an “S” when seen in a crosssectional view. In some embodiments the coiled collagen carrier maycomprise only one outer winding and in such instances the winding beingreferred to as outer windings is preferably this single outer winding.

The coiled collagen carrier comprises a collagen layer. The collagenlayer can be made from any suitable collagen, such as e.g. a collagenfoam or sponge, such as e.g. the commercially available Nycomed“TachoTop” product. A preferred collagen type is equine collagen, suchas e.g. native equine collagen extracted from sinews or human collagen,such as a solidified human collagen foam. The coiled collagen carrieralso comprises a coating layer on top of the collagen layer, whichcomprises thrombin and fibrinogen. The thrombin is preferably mostlysolid or solid. The fibrinogen is preferably mostly solid or solid.Preferably both the thrombin and fibrinogen are solid. Preferably thecoating also comprises riboflavin, which provides a yellow colour andenables the medical practitioner to determine which side of the collagencarrier is the active side.

In preferred embodiments of the present invention, at least the outerwindings or each winding of the coiled collagen carrier is orientated sothat the coating layer constitutes the inner surface of each winding. Inother embodiments of the present invention, each winding or at least theouter windings of the coiled collagen carrier is/are orientated so thatthe coating layer constitutes the outer surface of each of saidwindings.

In an embodiment of the present invention, the collagen carrier ispreferably a layered construction, for example consisting of a layer ofcollagen and a coating layer on top of the collagen layer.

The coiled collagen carrier of the present invention is form-stable.This can for example mean that the coiled collagen carrier isform-stable in the sense that it does not un-coil “when at rest”. In oneembodiment of the present invention, the form-stability of the coiledcollagen carrier diminishes when moisture is applied to it by which ismeant that the product becomes more flexible (i.e. less form-stable). Ina preferred embodiment of the present invention, the form-stability ofthe coiled collagen carrier is provided substantially only by thecoating. At least some of the form-stability of the coiled collagencarrier can in one embodiment be provided by the outer most winding ofthe carrier. In one embodiment of the present invention, theform-stability of the coiled collagen carrier is provided by a region atthe edge of the coiled collagen carrier adhering to the subjacentwinding. In an embodiment of the present invention, the form-stabilityof the coiled collagen carrier is provided by the coiled collagencarrier having no mechanical tension. In an embodiment of the presentinvention, the form-stability of the coiled collagen carrier is providedby outbalancing mechanical tension acting to un-coil the coiled collagencarrier by an adherence between the windings. In an embodiment of thepresent invention, the form-stability of the coiled collagen carrier isprovided by the coil having a elasticity module of 5-100 N/cm².

In one embodiment of the present invention, the form-stability isprovided by the coiled collagen carrier forming a brittle coil which,when subjected to stress, breaks without significant deformation.

In a preferred embodiment of the present invention, the coiled collagencarrier in an unrolled configuration is a (preferably rectangular orsquare-shaped) sheet, preferably having a width, a length and athickness. Preferably, said unrolled collagen carrier is a rectangularor square sheet. Preferably the sheet has a thickness of between 0.5 mmand 10 mm, such as e.g. 0.5-8 mm, for example 0.5-6 mm. In a preferredembodiment of the present invention, said thickness is preferably 1-4mm. such as preferably 1-3 mm. The thickness can in one embodiment be atthe most 4 mm, or at the most 5 mm, or at the most 6 mm, or at the most7 mm. The unrolled collagen carrier preferably has a surface area on itstop surface (which preferably is coated with the coated layer) of 4-100cm², more preferably 5-75 cm²′ such as 10-50 cm², such as e.g. 20-30cm², for example 25 cm² which can e.g. be given by a top surface of a 5cm×5 cm square collagen sheet.

In an embodiment of the present invention, the coiled collagen carriercomprises or consists of three, four or five windings.

In an embodiment of the present invention, the coiled collagen carrierhas a cylindrical shape with an outer diameter of less than 12 mm, suchas less than 11 mm, such as less than 10 mm, such as less than 9 mm,such as less than 8 mm, such as less than 7 mm, such as less than 6 mm,such as less than 5 mm, such as less than 4 mm, such as less than 3 mm.For example, the coiled collagen carrier has an outer diameter of 1-12mm, such as e.g. 3-11 mm, such as e.g. 5-10 mm, such as preferably 5-9mm, such as e.g. 6-8 mm.

In an embodiment of the present invention, the coiled collagen carrierhas an s-shaped inner most winding about the longitudinal axis of thecoiled collagen carrier.

It is preferred that the coating of the coiled collagen carrier coatinglayer has no through-going cracks, such as through-going cracks visibleby the naked eye.

The present invention further relates to a packed coiled collagencarrier, comprising the coiled collagen carrier according to the presentinvention arranged in a container. The container can for example besealed to prevent contamination and/or degradation and/or to maintainform-stability of the coiled collagen carrier. Preferably the containeris sealed to prevent contamination and/or absorption of liquid solventssuch as e.g. water. The container can in one embodiment further comprisea desiccant, such as silica gel, arranged in the container.

The container can in an embodiment comprise an inner container and anouter container. Preferably, the inner container comprises a cavityshaped as a segment of a cylinder, and wherein the curved part of thecylinder segment extends at least 180°, the cavity being sealed by atear-off or breakable foil. It is preferred that the outer containercomprises a sealed pouch inside which the sealed inner container isarranged together with a desiccant.

The packed coiled collagen carrier according to the invention can alsofurther comprise a label arranged to be visually inspected withoutopening the package and indicating whether the package with coiledcollagen carrier has been exposed to radiation sterilization, such as toX-rays, such as to high-energy X-rays, or such as to gamma radiation, orsuch as to electron beams, or such as to ultraviolet light. The labelcan for example be arranged on the outside of the outer container.

The packed coiled collagen carrier according to the invention can alsocomprise a sterile plastic bag with a minimal amount of air inside,preferably with no air being in the bag, the bag being especially suitedfor protecting the coiled collagen carrier from being activated bybodily fluids when using it in e.g. surgery. This is illustrated in FIG.10. This thin plastic bag may optionally be used after having un-packedthe packed coiled collagen carrier according to the invention.

An embodiment of the invention relates to a process according to theinvention, wherein ethanol is used for humidifying at least part of saidcollagen carrier.

An embodiment of the invention relates to a process according to theinvention, wherein said ethanol is applied in an amount of about0.8-10.4 mg/cm² of collagen carrier.

An embodiment of the invention relates to a process according to theinvention, wherein said ethanol is applied in an amount of about 0.8-6.1mg/cm² of said collagen carrier.

An embodiment of the invention relates to a process according to theinvention, wherein said ethanol is applied in an amount of about 1.2-4.7mg/cm² of said collagen carrier.

An embodiment of the invention relates to a process according to theinvention, wherein said ethanol is applied to at least one side of saidcollagen carrier that does comprise said coating, e.g said ethanol isapplied to at least one side of said collagen carrier, wherein said atleast one side comprises a coating.

An embodiment of the invention relates to a process according to theinvention, wherein said ethanol is applied to at least one side of saidcollagen carrier that does not comprise said coating.

An embodiment of the invention relates to a process according to theinvention, wherein said ethanol is applied to at least two opposingsides of said collagen carrier wherein at least one of said sidescomprises said coating.

An embodiment of the invention relates to a process according to theinvention, wherein said coating is externally oriented upon said rolledcompressed collagen carrier.

An embodiment of the invention relates to a process according to theinvention, wherein said coating is internally oriented upon said rolledcompressed collagen carrier.

An embodiment of the invention relates to a process according to theinvention, wherein said compression is performed using roller compactionwith a gap size between the rollers of no more than 1.0 mm, such as nomore than 0.9 mm, preferably no more 0.75 mm and wherein the diameter ofthe rollers are about 10-100 mm. As outlined herein, the gap-size may bekept constant or be allowed to increase during compression. Inembodiments where the gap-size increases during compression the abovelimits may be selected as the upper limits. In embodiments where thegap-size is kept constant, the above limits may be selected to be thoselimits.

An embodiment of the invention relates to a process according to theinvention, wherein said sterilization is performed using gammaradiation.

An embodiment of the invention relates to a process according to theinvention, wherein said collagen carriers are processed at 3-35° C. and5-80% RH (relative humidity).

An embodiment of the invention relates to a process according to theinvention, wherein said collagen carriers are processed at 18-22° C. and36-65% RH (relative humidity).

An embodiment of the invention relates to a process according to theinvention, wherein said drying results in said rolled compressedcollagen carrier comprising no more than 2.0% w/w (residual) ethanol.

An embodiment of the invention relates to a process according to theinvention, wherein said drying results in said rolled compressedcollagen carrier having no more than 1.6% w/w (residual) ethanol.

An embodiment of the invention relates to a process according to theinvention, wherein said drying results in said rolled compressedcollagen carrier comprising no more than 10.0% w/w (residual) water.

An embodiment of the invention relates to a process according to theinvention, wherein said drying results in said rolled compressedcollagen carrier comprising no more than 8.0% w/w (residual) water.

An embodiment of the invention relates to a process according to theinvention, wherein said coating comprises solid human fibrinogen in anamount of about 5.5 mg/cm² and solid human thrombin in an amount ofabout 2.0 IU/cm².

An embodiment of the invention relates to a process according to theinvention, wherein said rolled compressed collagen carrier has a loss ofcoating immediately after un-rolling of less than 0.6 mg/cm² as measuredby weighing.

An embodiment of the invention relates to a process according to theinvention, wherein said rolled compressed collagen carrier is at leastpartly mechanically processed, thereby providing an at least partlymechanically rolled compressed collagen carrier, such as a mechanicallyrolled compressed collagen carrier.

An embodiment of the invention relates to a process according to theinvention, wherein said collagen carrier has a density in the range of3.0-4.5 mg/cm³. The density of a collagen carrier of the presentinvention is the density of the collagen carrier excluding the coatinglayer.

An embodiment of the invention relates to a process according to theinvention, wherein said collagen carrier has a density in the range of3.0-4.5 mg/cm³.

Please note that the density of a collagen carrier of the presentinvention is the density of the collagen carrier excluding the coatinglayer.

An embodiment of the invention relates to a process according to theinvention, wherein said rolled compressed collagen carrier has a loss ofcoating immediately after un-rolling of less than 0.6 mg/cm² as measuredby weighing.

It should be noted that embodiments and features described in thecontext of one of the aspects of the present invention also apply to theother aspects of the invention i.e. all aspects relating to a rolledcompressed collagen carrier also apply to a compressed collagen carrier,or a rolled collagen carrier, or an unrolled rolled compressed collagencarrier.

All patent and non-patent references cited in the present application,are hereby incorporated by reference in their entirety.

The invention will now be described in further details in the followingnon-limiting examples.

BRIEF DESCRIPTION OF THE FIGURES

The present invention and in particular preferred embodiments thereofwill now be disclosed in further details with reference to theaccompanying figures. The figures show ways of implementing the presentinvention and are not to be construed as being limiting to otherpossible embodiments falling within the scope of the attached claim set.

FIG. 1 discloses schematically a preferred embodiment of an apparatusfor providing a coiled collagen carrier according to the presentinvention.

FIG. 2 shows the rotatable gripping means for gripping the collagencarrier along an edge and coiling the collagen carrier together withsome of its element for providing the gripping and the rotation; in theupper part of FIG. 2 the gripping means is shown in an exploded view andin the lower part of FIG. 2, a section of the gripping means is shown inassembled state,

FIG. 3 shows schematically guiding means for guiding a humidifiedcollagen carrier through a pair of rollers and to a support device,

FIGS. 4a and b each shows details of a preferred embodiment of anapparatus according to the present invention in a 3-dimensional view;FIG. 4b shows a close up of in particular the coiling device 5 shown inFIG. 4 a,

FIG. 5 discloses schematically a preferred layout of production facilityaccording to the present invention,

FIG. 6 shows a photograph of a coiled collagen carrier arranged in aninner container with a cover being partly removed, and

FIG. 7 shows a photograph a three coiled collagen carriers arrangedside-by-side on a flat surface.

DETAILED DESCRIPTION OF AN EMBODIMENT Apparatus

Reference is made to FIG. 1, which shows schematically a preferredembodiment of an apparatus 10 for providing a coiled collagen carrier.The apparatus comprises a number of elements as shown in the figure andcomprises in particular a device for applying moisture 2 to a collagencarrier 3 prior to coiling of a collagen carrier as disclosed herein.

The device for applying moisture 2 comprises a spray nozzle 4 directedtowards the surface of the coating layer of the collagen carrier, thespray nozzle 4 provides droplets as a mist or a spray of solvent. In thespray nozzle 4, droplets are produced assisted by sterile air, therebyethanol is mixed with sterile air. Thus, the collagen carrier isorientated with its coating surface facing upwardly towards the spraynozzle 4. The solvent penetrates into the coating of the collagencarrier 3 and softens the coating of the collagen carrier 3. It has beenfound that, it can be sufficient to humidify only the coating layer oran upper part thereof of the collagen carrier, although it is alsopossible to humidify the whole collagen carrier 3.

The apparatus 10 further comprises a coiling device 5, which is adaptedto grip the moisturised collagen carrier 3 along an edge and coil itinto a coiled collagen carrier 1. The coiling device 5 comprisesrotatable gripping means 6 for gripping the collagen carrier along anedge 7 of the collagen carrier 3 and coil the collagen carrier 3 byrotation of the gripping means 6 around an axis being parallel to thelongitudinal extension of the gripping means 6.

Gripping along the edge 7 and rotating the gripping means 6 allowscoiling of the collagen carrier into a desired shape, preferably withthe collagen carrier being supported during coiling. To assure coilingand assist in defining the shape of the coiled collagen carrier 1, thecoiling device 5 further comprises a support device 8 supporting thecollagen carrier while being coiled. The support device 8 is typically acavity arranged relatively to the gripping means 6 so that the surfaceof the support device 8 acts as counter pressure means by at least apart of the collagen carrier 3 abutting at least a part of the innersurface of the cavity during coiling. As mentioned, the shape of thesurface of the support device 8 at least assists in defining the shapeof the coiled collagen carrier 1.

The gripping device 6 comprises a pair of elongated members 9, such as apair of tweezers or pincers. The elongated members 9 has a longitudinalextension matching the width of the collagen carrier 1—the width of thecollagen carrier is considered to be the dimension parallel to theextension of the elongated members 9—whereby the collagen carrier isgripped at the edge along the whole width by the elongated members 9.

Gripping of the collagen carrier 3 is accomplished by decreasing thedistance between the two elongated members 9 once the collagen carrier 3is located in between the elongated members 9 to an extent providing agripping being sufficient to provide coiling once the elongated members9 are rotated.

As shown in FIG. 1, the support device 8 is a cavity comprising a bottompart shaped as a segment of a cylinder having at least one open endthrough which the elongated members extend, and wherein the curved partof the cylinder segment extends at least 180°—in the embodiment shown inFIG. 1, the cylinder segments extends 180°. The upper part of the cavityis constituted by two parallel straight wall segments 8 a so that thecavity has the shape of an open channel. The two wall segments 8 a mayalternatively be sloping slightly outwardly, such as in the order of 5°.

Thus, in the embodiment of FIG. 1, the cavity is channel-formed with twoparallel side walls 8 a extending from the bottom. This configuration ofthe cavity provides the channel with a generally “U”-shaped crosssection, the bottom forming the curved part of the “U”-shapedcross-section and each side walls 8 a forming the straight parts of the“U”-shaped cross section.

The elongated members 9 of the gripping device 6 extend into the cavityof the support device 8 through the open end. The elongated members 9are furthermore extractable so that once the collagen carrier 3 has beencoiled and is located in the cavity of the support device 8, theelongated members 9 are extracted from the coiled collagen carrier 1.The elongated members 9 are extracted in a direction being parallel tothe longitudinal extension of members. When another collagen carrier 3is to be coiled, the elongated members 9 are introduced back into thecavity of the support device 8 by moving the elongated members 9 in theopposite direction than during the extraction. Furthermore, theelongated members 9 are opened, that is the gap between the two membersis larger than the thickness of a humidified and compressed collagencarrier 3 so that the elongate members 9 are ready to receive a collagencarrier in between them. By extractable is preferably meant thatelongated members 9 can be removed from coiled collagen carrier afterthe coiling has been performed and in general also that they can beremoved from the position where coiling is performed. Thus, theextractable is considered to cover also re-tractable.

Thus, the apparatus of FIG. 1 is adapted to move the pair of elongatedmembers 9 in a reciprocating movement, so that the elongated members canbe retracted after the collagen carrier has been coiled.

It is often found that the coiled collaged carrier stays inside thesupport device 8 while the elongated members 9 are extracted. However,if extraction of the elongate members 9 results in that the coiledcollagen carrier moves out of the cavity with the elongate member 9, theapparatus may be fitted with a securing device e.g. limiting the size ofthe open end to a smaller dimension than the outer diameter of thecoiled collagen carrier. This may be implemented by shaping the open endof the support device 8 with a small stop block in the form of anelevation at the open end of the support device 8, or shaping the openend of the support device having such limited size or an diaphragm, aslotted element or the like may be arranged to prevent the coiledelement from be moved out of the support device while still allowextraction of the elongate members 9.

Thus, extraction of the elongated members 9 from the coiled collagencarrier 1 may involve securing of the coiled collagen carrier 1 insidethe cavity if the elongated members 9 do not slide easily out from thecoiled collagen carrier 1. Such securing may alternatively be providedby mechanically pressing the coiled collagen carrier toward the bottomof the cavity while extracting the elongated members, or a latticestructure may be arranged to prevent the coiled collagen member fromsliding out of the cavity through the open end of the cavity whileallowing extraction of the elongated members; thereby the draggingaction from the elongated members on the coiled collagen carrier 1 maybe outbalanced by the lattice structure, or the pressing action.

Once the collagen carrier has been coiled and the elongated membersextracted, the elongate members may be used re-align the coiled collagencarrier in the support device 8 by pushing the coiled collagen carrierback into the centre of the support device, in cases where theextraction of the elongated members has shifted the position of thecoiled collagen carrier towards the open end of the support device.

As indicated in FIG. 1, the result of the coiling is a coiled collagencarrier in the form of elongated member with an “S”-shaped core. The twocurves of the “S” are defined by the elongated members 9. Furthermore,the rotation of the gripping device 6 is adapted to arrange the edge 14so that it abuts the wall of the cavity when coiling is completed andthe elongate members 9 are to be extracted. This means that the rotationof the elongate members is stopped when the entire collagen carrier 3has been coiled and the 14 edge of the coiled collagen carrier 1 isorientated so that it abuts the wall of the support device 8. Therebyun-coiling after coiling may be prevented.

The apparatus 10 further comprises a compressing device 11. Thecompressing device 11 being arranged to compress the moisturisedcollagen carrier 3 prior to coiling of the moisturised collagen carrier,that is as indicated in FIG. 1, the compressing device being arrangedafter the device for applying moisture 2 and before the coiling device5.

The compressing device comprises a pair of rollers 12 having a gap sizebeing smaller than the thickness of the collagen carrier 3 beforepassing through the set of rollers 12 and being arranged to compress themoisturised collagen carrier 3 prior to coiling of the moisturisedcollagen carrier. The compression being provided because the gap inbetween the rollers is smaller than the thickness of the moisturisedcollagen carrier. As indicated in FIG. 1, the rollers 12 rotate inopposite directions so as to transport the collagen carrier through thepair of rollers 12 towards the coiling device 5.

The gap size between the rollers is selected so as to provide thedesired compression ratio. Typically and preferred numbers for the gapsize is no more than 0.5 mm, preferably no more than 0.6 mm or between0.5-1.0 mm, or no more than 0.75 mm. However, the gap size should beselected in accordance with the thickness of the collagen carrier 3 soas to obtain the desired compression ratio.

The compression device may preferably include a certain flexibilityallowing the compression ratio to be influenced by the collagen carrierand rendering the compression device more suited for handling collagencarriers of different densities. In the embodiments shown in FIG. 1where the compression device comprises a set of rollers 12, this isimplemented by allowing the rollers to move apart each so that the gapsize increases. The movement of the rollers to increase the gap size iscaused by the collagen carrier pressing on the surface of the rollersduring its passage through the gap. Mechanically this is implemented byallowing some flexibility in the means used for mounting the rollers orby mounting one or both rollers 12 in a manner allowing displacement ofthe rollers in a direction being perpendicular to the axis of rotationand biasing the rollers towards each other by springs.

FIG. 2 shows the rotatable gripping means for gripping the collagencarrier along an edge and coiling the collagen carrier together withsome of its element for providing the gripping and the rotation; in theupper part of FIG. 2 the gripping means is shown in an exploded view andin the lower part of FIG. 2, a section of the gripping means is shown inassembled state. The gripping means comprises a pair of tweezers orpincers forming the elongated members 9. These elongated members have atone end an L-shape element 9 a, 9 b. In the corners of the L-shapedelements pivoting studs 21 is provided which fit into correspondingpivoting openings 23 of the assembling element 20. When the L-shapedelements 9 a, 9 b are arranged in the assembling element 20, the shorterlegs 9 b of the L-shape elements protrudes out from the assemblingelement 20 in a direction being perpendicular to the longitudinaldirection of the shaft 16. The longer legs 9 a protrude also from theassembling element but in direction being aligned with the longitudinaldirection of the shaft 16.

The gripping movement of the elongated members 9 are provided byapplying a force to the protruding parts 9 b of the L-shaped elementswhich will cause the L-shaped elements to pivot around the pivotingstuds 21 whereby the elongated members 9 will move towards each other.Movement of the elongated member 9 to provide release is provided bymoving the protruding parts of the L-shaped elements in oppositedirecting, that is pivoting the L-shaped elements in opposite directionthan to accomplish the gripping.

To assist gripping, a spring 22 is applied to the L-shaped elements asshown in the lower part of FIG. 2, which springs are pre-tensioned tokeep the elongated members 9 biased towards each other (in a grippingposition). It is noted that the spring 22 at the upper part isconstituted by two parallel extending pins so (see e.g. the lower partof FIG. 2) so that the spring acts as a clamp spring. The assemblingelement 22 is mounted on a shaft 16 by use of a pin bolt 17 whichpenetrates through the assembling element 20 and fits into a recess 24provided in the part of the shaft 16 protruding into the assemblingelement 20. The pin bolt is fixated by use of a lock ring 18. The recess24 is provided off-centre of the shaft 16. The shaft 16 is arranged in adevice which rotates the shaft and provides a reciprocating movement ofthe shaft 16, and as the assembling element 22 is fixed relatively tothe shaft 16 a reciprocating movement and rotation of the shaft 16results in that the elongated members 9 also performs these movements.

The rotation of the shaft 16 is preferably performed by use of a steppermotor so that the angular position of the shaft is well-defined andthereby also the number of revolutions performed.

After the collagen carrier 3 has been coiled into a coiled collagencarrier it is still moisturised (contains solvent) and is stillsoftened. To provide a form-stable coiled collagen carrier 1, thecollagen carrier is de-moisturised which is provided by drying thecoiled collagen carrier 1. The apparatus accordingly further comprisingat least a drying means (not shown in the figure) for drying one or morecoiled collagen carriers subsequently to the coiling.

The drying means may typically be embodied as a drying tunnel throughwhich the coiled collagen carrier 1 passes and inside which dryingtunnel the temperature is elevated relatively to the temperature of thecoiled collagen carrier 1 and the relative solvent content in the air iskept low. These two measures (elevated temperature and low relativesolvent content) promote transport of solvent from the coiled collagencarrier 1 to the air inside the drying tunnel. Forced circulation of theair may advantageously be applied to enhance removal of solvent from thecoiled collagen carrier 1.

The drying means comprises a pump (not shown in FIG. 1) sucking orblowing air, preferably being sterile filtered. It is noted, that themain purpose of the drying means is to remove excess solvent applied induring the moisturizing of the collagen carrier and that this solvent isdifferent from water.

The apparatus may comprise means for applying heat inside the dryingtunnel. However, in the cases that the solvent used is highly flammable(e.g. ethanol and/or isopropanol) care should be taken to avoidexplosion and/or fire which could be introduced by such heating means.

The direction of the air being sucked or blown though the drying tunnelis typically either counter current to the conveying direction of thecoiled collagen carriers or is in the same direction as the conveyingdirection of the coiled collagen carriers.

In a preferred embodiment of the apparatus, the purpose of the dryingtunnel is to reduce the Ethanol content in the coiled collagen carrier.

After the coiled collagen carriers has been dried in e.g. the dryingtunnel for preferably about 30 minutes, the coiled collagen carriers maybe further dried e.g. by arranging the coiled collagen carriers in asealed box together with a desiccant. The coiled collagen carriers arepreferably present in the sealed box for up to 72 hours.

The water content, if present, is reduced at a later time point when thecoiled collagen carrier is placed in a container over a desiccant andarranged in an outer container.

Preferably, the air is sucked into the drying tunnel form the ends by acentrally placed fan above the machine—counter current to the directionin which the fleeces are being moved (this is preferred to minimize therisk of explosions outside of the drying tunnel). For the drying phasesfor reduction of Ethanol, the preferred requirement is to have thehumidity of the air inside the drying tunnel as the same as the overallrequirements for the humidity in the room in which the machine is placedthat is typically 30-50% RH and 18-22° C.

The apparatus is advantageously embodied so as to provide an automatedproduction of coiled collagen carriers 1. As indicated in FIG. 1, theapparatus is embodied as an assembly line which conveys the collagencarriers 3 through the various production stages.

Thus, apparatus 10 comprises a first conveyer device 13 which conveyscollagen carriers 3 prior to coiling past the moisturiser device 2 andto the coiling device 5.

On its way from the moisture device 2 and to the coiling device 5, themoisturised collagen carriers 3 pass through the pair of rollers 12arranged to compress the moisturised collagen carrier prior to coilingof the moisturised collagen carrier, and the first conveyer device 13conveys the moisturised collagen carriers 3 to the pair of rollers 12.It is noted that conveying of the moisturised collagen carrier 3 fromthe end of the first conveyer device 13 and to the gap between the pairof rollers 12 can be assisted by guides (see FIG. 3) which guide themoisturised collagen carriers 3 to the pair of rollers 12. As acompression is performed by the pair of rollers 12, the rotation of therollers 12 conveys the moisturised collagen carrier 3 through thecompression device 11 and to the coiling device 5. Again, suitableguiding means (see FIG. 3) may be applied to guide the collagen carriers3 to the position in the cavity of the coiling device 5 in which thegripping means 6 may grip the collagen carrier along an edge and coilthe collagen carrier 3. The guides and guiding means are made from aninert material that does not contaminate the collagen carriers by e.g.rubbing off of material.

Although the first conveyer device 13 is shown as a single conveyer 13belt, the first conveyer device preferably comprises two conveyingelements, preferably in the form of two separate conveyer belts. One ofthese conveying elements (first conveying element) is used for conveyingthe collagen carrier towards the moisturiser device 2 and a subsequentconveying element (second conveying element) for conveying the collagencarrier past the moisturiser device 2 and to a guiding means (see FIG.3) and thereby to the pair of rollers 12. The two conveying elements arecontrolled so that a collagen carrier which has not yet been moisturisedis only conveyed to the second conveying element that conveys it pastthe moisturiser device in situations where the compression device 11 andthe coiling device 5 is ready to receive a moisturised collagen carrier;that is in situations where the compression device 11 and the coilingdevice 5 are not compressing or coiling another moisturised collagencarrier. This has inter alia the advantage that the moisturised collagencarrier does not go through any unnecessary waiting time which couldresult in evaporation of solvent and/or undesirable changes of themoisturised collaged carrier due to be moisturised.

The guiding means for guiding the moisturised collagen carrier 3 to thepair of roller 12 and for guiding the compressed and moisturisedcollagen carrier 3 to the coiling device 5 is shown schematically inFIG. 3. The guiding also conveys the collagen carrier. The guiding meanscomprises an upper guiding part 30, 31 and a lower guiding part 32, 33.

The upper guiding part comprises two sets of wheels 30, 30 a and 30, 30b and conveyer belts arranged on the wheel pairs in the form of rubberbands 31 with a circular cross sections. The wheel 30 a forms part ofthe first conveyer element of the first conveyer device 13 and rotatesalong with the movement of the second conveyer element. The wheel 30rotates in a manner so that the speed of the conveyer belts 31 inbetween which the moisturised collagen carrier is present aftermoisturising is equal. As also shown in FIG. 3, the upper guiding partforms a funnel shape passage tapering towards the pair of rollers 12.The speed of the conveyer belts 31 is furthermore equal to the angularvelocity of the rollers 12. The reason for equalising the speed of themoving elements of guiding means and the rollers is to avoid shearingforces to be applied to the surface of the collagen carrier.

The lower guiding part comprises two set of wheels each set comprisingthree wheels in a double triangular configuration as depicted in FIG. 3.The conveyer belts 33 in the form of rubber bands are arranged on thewheels 32. The conveyer belts 33 are moved by one of the wheels of eachpair is actively rotated while the remaining two wheels arefree-wheeling. The conveyer belts 33 thereby defines a passage below thegap between the pair of roller 12 into which the collagen carrierproceeds after being compressed.

In both the upper and lower guiding parts, the conveyer belts 31 and 32are each constituted by two parallel rubber bands distanced apart with adistance being smaller than the width of the collagen carrier so as toincrease the support of the collagen carrier while being conveyed.

Due to the definition of the passages above and below the pair ofrollers, the path the collagen carrier may follow is spatiallyrestricted by the conveyer belts 31, 33.

Furthermore, to assist the automated production of coiled collagencarriers 1, the cavity of the coiling device 5 is formed in a secondconveyer device. While the first conveyer device 13 conveys the collagencarrier 3 at a constant speed, the second conveyer device typicallyconveys coiled collagen carriers 1 step wise; that is as long as thecoiling takes place, the second conveyer device is at rest and oncecoiling is finished (the edge 14 is arranged so as to abut the surfaceof cavity and the elongated members 9 extracted) the second conveyerdevice moves to arrange an empty cavity below the pair of rollers and infront of the extracted elongated members 9.

The conveying speed of the first conveyer device is set in accordancewith the amount of solvent being applied from the nozzles 14 to obtain apredefined amount solvent applied per surface area of the collagencarrier 3.

In many of the preferred embodiments, the cavity is formed in a trayhaving a plurality of cavities and said tray being arranged on andconveyed by a second conveyer device of the apparatus. Thus, theformulation “the cavity of the coiling device 5 is formed in a secondconveyer device” includes embodiments where the cavities are provideddirectly in e.g. a conveyer belt and where the cavities are provided ina tray.

Such trays, which generally are preferred, are arranged on a conveyerbelt in a manner where the position of the trays relatively to theconveyer is known and fixed. Typically, the conveyer belt conveyer belthas teeth which co-operates with indentations or notches in the tray sothat the tray is moved along with the conveyer belt in a mutually fixedposition.

The trays are often made stackable so that they can be stacked whilecontaining coiled collagen carriers in the cavities without the coiledcollagen carrier being abutted by e.g. tray arranged above in a stack.This is often accomplished by making the cavities deeper than thediameter of the coiled collagen carrier and longer than the length ofthe coiled collagen carrier.

It is often preferred to use disposable trays and such disposable traysare often made from plastic, such as PET, and produced by moulding.However, the tray may also be made of metal in which case, they may bereused by cleaning and sterilization e.g. by use of an autoclave.

The orientations and mutual arrangements of the various parts presentedin FIG. 1 are implemented in the apparatus as implemented in the figure.That is, the first conveyer device 13 is arranged above the coilingdevice 5 with the pair of rollers 12 arranged in between.

Explosion or risk of fire may be a critical issue to consider as thecollagen carrier is humidified with a flammable solvent such as ethanoland/or isopropanol Furthermore, contamination of the collagen carriersmay often an issue that must be taken care of during humidification,compression, coiling and drying. Mainly to limit the explosion riskand/or risk of fire and to some extend also to avoid contamination, thevarious parts used for producing the coiled collagen carrier areshielded from the environment by a cabinet. Thus, the apparatus maytypically comprise a cabinet sealing the moisturiser device 2, and/orthe pair of rollers 12, and/or the coiling device 5, and/or the supportdevice 8, and/or the first 13 and/or the second conveyer device.

As the solvent in some instances is highly flammable, the apparatus mayadvantageously comprise suction means for sucking out gas and/ordroplets originating from the humidification as well as a closed cabinetwith a defined socall ATEX zone.

After the collagen carrier 3 has been coiled they are still present inthe cavities of the support device. The coiled collagen carriers 3 areto be packed in a suitable package and the apparatus comprising a devicefor conveying a coiled collagen carrier from the supporting device andarranging it in a container forming the packaging for the coiledcollagen carrier.

Prior to packaging the coiled collagen carrier 3 in suitable package,the collagen carriers are further dried to further dry off solvent andwater (if present). This is done by arranging the collagen carriers 3 insuitable sealed containers together with a desiccant and leave them atrest for 72 hours. The desiccant will during that period absorb furthersolvent and water.

The packaging for the coiled collagen carrier comprises in manypreferred embodiments two containers and a desiccant. The two containersare an outer container and inner container. The inner container containsthe coiled collaged carrier and is arranged together with a desiccantinside the outer container.

The inner container has a compartment with an opening, inside whichcompartment the coiled collagen carrier is arranged manually. However,the arrangement may be carried out by a robot which grasps a coiledcollagen carrier located in a cavity of the support device and moves itinto the compartment of the inner container through the opening.

The apparatus typically has a cover arranging device, in the form ofrobot, which arranges a cover to at least cover the opening of the innercontainer. The apparatus has a welding or gluing device to facilityattachment of the cover to the inner container.

The material of the cover attached to the inner container is permeableto gas and/or liquid and once the coiled collagen carrier is arranged inthe inner container and the cover attached, the inner container may bearranged in the outer container.

To accomplish the transfer of the inner container to outer container,the apparatus may have a device arranging the inner container in theouter container. This device is typically in the form of a robot. Theouter container is made from a non-permeable material and closed in asealed manner. The closing of the outer container is provided by a heatwelding device or a gluing device closing the outer container by heatwelding or gluing.

As the outer container is closed in a sealed manner and the coiledcollagen carrier may still container some solvent and/or water, adesiccant is arranged inside the outer container and outside the innercontainer as disclosed above. The main purpose of the desiccant is totake up water absorbed by th coiled collagen carrier during packagingbut may also absorb water permeating through the cover applied to theinner container and/or water being trapped inside the outer container ingeneral. The desiccant is arranged by a device designed for thispurpose.

As disclosed above, the apparatus may have devices for conveying and/orarranging the coiled collagen carrier, the cover, the desiccant and/orthe inner container. These devices are preferably robots such as anumerically controlled robot arm with gripping means. The gripping meansmay be robot claws, sucking disc and the like.

The automated handling of the coiled collagen carrier to arrange thepack the coiled collagen carrier may be replaced by a manual handling.However, in order to maintain a sufficient production speed, unifiedquality and avoid contamination the automated handling is oftenpreferred.

Although great care is taken during in the process of coiling andpacking, there might still be a risk that the packed coiled collagencarrier may be contaminated with e.g. germ. The apparatus mayaccordingly further comprise a sterilizing device arranged to sterilizethe packed coiled collagen carrier. Such a sterilizing device istypically embodied as a source of radio magnetic radiation adapted toradiate the electromagnetic radiation towards and through the packedcoiled collagen carrier, that is towards and through the outercontainer, the desiccant, the cover, the coiled collagen carrier and thecoiled collagen carrier. Alternatively, the sterilizing may be performedremote from the apparatus, e.g. by shipping the collagen carriers eitherbeing packed or not packed to a sterilization department remote from theproduction site for coiled collagen carriers.

As the quality of the coiled collagen carrier often has to fulfilcertain prescribed criteria the apparatus may comprises elements thatmonitor e.g.

-   -   the physical appearance of the coiled collagen carrier (lack of        e.g. coating is often visually identifiable),    -   whether a coiled collagen carrier is present in the inner        container before a cover is attached,    -   whether a desiccant is present in the outer container before the        inner container is arranged therein and the outer container is        closed,    -   whether production details such as batch number, production date        etc is printed on certain parts of the container(s),    -   whether the packed coiled collagen carrier has been sterilized.

Such elements for monitoring may be image recognition devices adapted toimage the processing of the apparatus at preselected stages, examine theimages and signal a discard signal for a coiled collagen carrier in casethe examining reveals that a coiled collagen carrier falls outsidequality ranges. For instance, if the image recognition device detectsthat no coiled collagen carrier is present in the compartment of theinner container, the device sends a discard signal to an supervisingcomputer which in turn activates a discard of the inner container so asto avoid further handling of that particular inner container (as thiswould otherwise result in that the final closed outer container wouldnot contain any coiled collagen carrier).

As disclosed above, it is often desirable to control the atmospheresurrounding the collagen carrier during forming it into a coiledcollagen carrier and during packaging. In order to accomplish that, theapparatus may be equipped with air-conditioning devices maintaining theatmosphere surrounding the collagen carrier and humidification device atleast while being humidified, compressed and coiled at a temperature of18-22° C. and a relative humidity of 30-50%.

Reference is made to FIG. 4 which shows schematically how a productionfacility according to the present invention may be divided into aprimary production room and a secondary production room. The primaryproduction room contains the operation necessary to provide produce acoiled collaged collagen carrier from a collagen carrier and arrangedthe coiled collagen carrier in an inner container with a cover. As thecollagen carrier in the primary production room is unprotected from e.g.contamination until it is arranged in the inner container and a cover isarranged to the inner container, the demands to sterility etc in theprimary production room are high.

It should be noted that although the cover applied to the innercontainer constitutes some kind of barrier, the cover is made from apermeable material that does not provides a barrier through whichcontamination may not pass through. However, once the coiled collagencarrier is arranged in the inner container and the cover applied, therisk of contamination and cross contamination in between coiled collagencarriers is lowered. Furthermore, as each handling of the coiledcollagen carrier may represent a risk of contamination, it is desirableto divide the production facilities into separate rooms.

Accordingly, the elements of the apparatus according to the presentinvention taking part in providing a coiled collagen carrier andarranging the coiled collagen carrier in an inner container with a coverare arranged in a primary production room being sealed by airlocks.

Furthermore, the elements of the apparatus taking part in arranging theinner container and desiccant in a second outer container, sealing theouter container and sterilising the packed coiled collagen carrier arearranged in a secondary production room sealed by airlocks.

In the embodiment shown in FIG. 4, the primary and secondary productionrooms are connected by a conveyer extending in between the twoproduction rooms and comprising an airlock whereby the inner containerbeing conveyed by the conveyer from the primary production room to thesecondary production room.

FIG. 4 shows details of a preferred embodiment of an apparatus accordingto the present invention in a 3-dimensional view. The same numerals asused in relation to FIGS. 1-3 are also used in FIG. 4. As shown infigure, the first conveyer device 13 comprises a first conveyer element13 a and a second conveyer element 13 b. The moisturising device 2 isencircled by a line labelled 2 above the second conveyer element 13 b.

The guiding means for guiding the moisturised collagen carrier 3 (notshown) to the pair of roller 12 and for guiding the compressed andmoisturised collagen carrier 3 to the coiling device 5 is above thesupport device 8. In the embodiment shown in FIG. 4, the support device8 is a separate element, a tray, comprising sixteen cavities, and thesupport device 8 is arranged on and conveyed by a second conveyer device34 (the arrows along the conveyer belt of the second conveyer device 34indicates the direction of the movement of the belt).

As also shown in FIG. 4, the second conveyer device extends into adrying tunnel 35 (as disclosed herein). Air is sucked or blown into thedrying channel through an opening (not shown) arranged midway downstreamof the drying tunnel and the air escapes (when blowing) or enters (whensucking) through the opens ends of the drying tunnel. A further tunnelis arranged in the region of the opening inside the drying tunnel,through which further tunnel the support device 8 pass. The purpose ofthe further tunnel is to hinder air being blown out of or suck into thedrying tunnel 35 flom blowing the coiled collagen carriers out of thesupport device 8. The further tunnel acts as an air distributer whichdistributes the air flow along the space defined by the outer surface ofthe further tunnel and in the inner side of the drying tunnel 35.

A trough 36 with suction is applied below the coiling device 5 toventilate the apparatus at least in the region of the coiling device.

As shown, the guiding means comprises an upper guiding part 30, 31 and alower guiding part 32, 33. The upper guiding part comprises two sets ofwheels 30, 30 a and 30, 30 b and conveyer belts arranged on the wheelpairs in the form of rubber bands 31 with a circular cross sections. Thewheel 30 a forms part of the first conveyer element of the firstconveyer device 13 and rotates along with the movement of the secondconveyer element. The wheel 30 rotates in a manner so that the speed ofthe conveyer belts 31 in between which the moisturised collagen carrieris present after moisturising is equal. As also shown in FIG. 4, theupper guiding part forms a funnel shape passage tapering towards thepair of rollers 12. The speed of the conveyer belts 31 is furthermoreequal to the angular velocity of the rollers 12. The reason forequalising the speed of the moving elements of guiding means and therollers is to avoid shearing forces to be applied to the surface of thecollagen carrier.

The lower guiding part comprises two set of wheels each set comprisingthree wheels in a double triangular configuration as depicted in FIG. 3.The conveyer belts 33 in the form of rubber bands are arranged on thewheels 32. The conveyer belts 33 are moved by one of the wheels of eachpair is actively rotated while the remaining two wheels arefree-wheeling. The conveyer belts 33 thereby define a passage below thegap between the pair of roller 12 into which the collagen carrierproceeds after being compressed.

In both the upper and lower guiding parts, the conveyer belts 31 and 32are each constituted by two parallel rubber bands distanced apart with adistance being smaller than the width of the collagen carrier so as toincrease the support of the collagen carrier while being conveyed.

FIG. 4b shows a close up of in particular the coiling device 5 shown inFIG. 4a

The elements in FIG. 4 labelled 37 are sensors, typically being opticalsensors and the line of sight being indicated, arranged to monitor thevarious steps performed by the apparatus.

Processes

The apparatuses disclosed herein are adapted to perform a process forcoiling a collagen carrier comprising a collagen layer and a coatinglayer comprising mostly solid fibrinogen and mostly solid thrombin. Inthe following, preferred embodiments of processes according to thepresent invention will be disclosed. Reference is made to FIG. 1 and theelements and parts presented therein are referenced by referencenumbers—this is not intended to limit the processes to the apparatusdisclosed in FIGS. 1, 2, 3 and 4.

Processes according to the invention typically comprise the sequentialsteps of humidifying at least part of a collagen carrier 3, and coilingthe collagen carrier 3 by gripping the collagen carrier 3 between a pairof elongated members 9, and rotating the pair of elongated members 9about an axis being parallel to a longitudinal extension of theelongated members 9 in order to coil the collagen carrier 3 on themembers, while the collagen carrier 3 is supported by a support device8.

The humidifying and coiling steps are preferably executed as twoseparate steps as disclosed above in relation to the embodiment of theapparatus 10, which steps are executed consecutively to each other. Thetime between humidifying and coiling is selected so that the softeningeffect obtained by the humidification on the collagen carrier 3 ispresent while the collagen carrier 3 is coiled.

After the collagen carrier 3 has been coiled, the process involves astep of drying the coiled collagen carrier 1. The drying steps removessolvent from the coiled collagen carrier and the drying step istypically and preferably performed while the coiled collagen carrier issupported so as to maintain its coiled shape during drying. The resultof the process is a form-stable coiled collagen carrier 1.

The coiling is performed by gripping the collagen carrier using at leastone gripping device and the collagen carrier is gripped along an edge ofthe collagen carrier 3. The coiling is performed by gripping thecollagen carrier using at least one pair of tweezers or pincers 9.

Drying of the coiled collagen carrier 1 is typically performed byblowing air with humidity lower than the coiled collagen carrier andoptionally applying heat to the air to enhance e.g. evaporation of theliquid used to humidify the collagen carrier 3. It is noted that theterm humidity is to be understood broadly and not limited only to water.For instance, humidity is also used to cover the concentration in theair of the solvent used to humidify the collagen carrier 3.

As noted above, the process involves humidifying at least a part of thecollagen carrier and in some embodiments of the invention the part beinghumidified is the coating layer. Typically, the humidification step isperformed by spraying droplet of liquid onto the surface of the coatinglayer, and the humidification is obtained by the liquid penetrating intothe coating layer of the collagen carrier 3 e.g. by a capillary action.Thus, the amount of liquid present in e.g. the coating layer may varywith the depth; however, as one aim of humidifying is to soften thecollagen carrier 3 such variations in liquid amounts are acceptable. Inmany preferred embodiment, the coating layer has been humidified using asolvent applied onto the surface of the coating layer in an amount1.2-10.75 mg/cm² surface of collagen carrier 3. The solvent usedtypically comprises or consists of ethanol.

A process according to the present invention may further comprise a stepof compressing the collagen carrier 3 which compression reduces thethickness of the collagen carrier. While different compression ratio,i.e. ratio between the thickness of the collagen carrier 3 before andafter compression, may vary, the collagen carrier is preferablycompressed with a compression ratio between 6 and 12. The compression isperformed after the humidifying step and before the coiling step, thatis the compression is performed prior to coiling of the collagencarrier.

An efficient compression has proven to be performed by passing thehumidified collagen carrier through a set of rollers 12 having a gapsize being smaller than the thickness of the collagen carrier 3 beforepassing through the set of rollers 12. The gap size is selected so as toprovide the desired compression ratio. Typically and preferred numbersfor the gap size is no more than 0.5 mm, preferably no more than 0.6 mmor between 0.5-1.0 mm, or no more than 0.75 mm. However, the gap sizeshould be selected in accordance with the thickness of the collagencarrier 3 so as to obtain the desired compression ratio.

After the collagen carrier 3 has been humidified, optionally compressedand coiled, the coiled collagen carrier 1 is still softened and may havea tendency to un-coil during drying e.g. due to gravity effects and/orsome mechanical tension in coiled collagen carrier 1. To assure that thecoiled collagen carrier 1 hardens in the coiled shape, the edge (seenumber 14 in FIG. 1) of the coiled collagen carrier 1 arranged on theoutside of the coil after coiling is abutting the surface of the cavityand thereby being fixated by the support device 8 relatively to thecoiled collagen carrier 1 during drying. It is noted that fixated refersto that the coiled collagen carrier 1 being orientated in a pre-definedorientation relatively to the support device and that preferably nofurther means, such as straps, pressing means or the like, are appliedto fixate the coiled collagen carrier

Once the coiled collagen carrier 1 has dried the softened parts of thecollagen carrier has hardened and the coiled collagen carrier 1 isform-stable. The collagen carrier is typically said have been dried whenis have passed through the drying tunnel and have been arranged in asealed container for about 72 hours together with a desiccant.

The support device 8 is as disclosed above with reference to FIG. 1 acavity having a bottom part shaped as a segment of a cylinder having atleast one open end through which the elongated members extend into thecavity, and wherein the curved part of the cylinder segment extends atleast 180°. During the coiling process, the outer edge 14 of thecollagen carrier is arranged inside the part of the cavity formed as asegment of cylinder and the edge 14 abuts the inner surface of thecavity. Once the edge 14 abuts the inner surface, the coiling process isterminated and the gripping means in the form of a pair of elongatedmembers 9 is extracted from the coiled collagen carrier through the openend of the cavity.

Prior to coiling, the elongated members 9 are positioned in the cavityin the support device in a predefined position where the elongatedmembers are ready to receive a collagen carrier. Furthermore, theelongated members 9 are opened in the sense that the gap between theelongated members 9 is larger than the thickness of a humidified andcompressed collagen carrier.

Extraction of the elongated members 9 from the coiled collagen carrier 1may involve securing of the coiled collagen carrier 1 inside the cavityif the elongated members 9 do not slide easily out from the coiledcollagen carrier 1. Such securing may be provided by the means disclosedabove in relation to the apparatus shown in FIG. 1

Once the elongated members 9 are extracted, any securing may bereleased. The extraction of the elongated members 9 is typicallyperformed before drying of the coiled collagen carrier. The pair ofelongated members may be constituted by a pair of tweezers and theprocess disclosed above is the same.

The atmosphere surrounding the collagen carrier 3 and humidificationdevice 2 while the collagen carrier 3 being humidified, compressed andcoiled is typically maintained at a temperature of 18-22° C. and arelative humidity of 30-50%. After the coiled collagen carrier 1 hasbeen dried to form a form-stable collagen carrier, the process mayinclude the step of arranging the form-stable coiled collagen carrier 1in a container and subsequently sealing the container. The step ofarranging the coiled collagen carrier in a sealed container prevents thecoiled collagen carrier 1 from being humidified and/or contaminated.Furthermore, the step of arranging the coiled collagen carrier 1 in asealed container may also comprise the steps of arranging the coiledcollagen carrier 1 in an inner container and arranging the innercontainer in an outer container. In addition, a desiccator may bearranged inside the outer container prior to sealing of the container.

While an aim of the process is to provide a sterile coiled collagencarrier packed in one or more containers, the process may also include asterilizing step during which the container(s) with coiled collagencarrier is exposed to a sterilizing process. The sterilizing maytypically be radiation sterilization. To make it easy detectable whethera given coiled collagen carrier 1 has been sterilized, a labelindicating whether sterilization has been carried out or not may bearranged on the outside of the outer container—or container in general.

An often preferred sterilization step comprises sterilizing the coiledcollagen carrier 1 using gamma radiation. The sterilization of thecoiled collagen carrier 1 is often performed to a sterility assurancelevel (SAL) of 10⁻⁶ using gamma radiation.

Similarly to what was disclosed in relation to the apparatus accordingto the invention and with reference to FIG. 5 the process according tothe present invention may be divided into a process carried out in aprimary production room and a secondary production room. This means thatin preferred embodiments, the arranging of the form-stable coiledcollagen carrier in the inner container and closing inner container isperformed in a primary production room and the arranging of the innercontainer in an outer container is performed in a secondary productionroom; the first and the secondary production room be connected with eachother by an airlock and the closed inner container is transported fromthe first to the second room via the airlock.

The process carried out in the secondary production room may furthercomprise the step of arranging a desiccator inside the outer containerprior to sealing of the container and the step of sterilizing the coiledcollagen carrier.

A process according to the present invention is typically carried out asan assembly-line process in which the collagen carrier is conveyedwithout intermediate storing between humidifying and coiling and betweencoiling and drying.

Furthermore, it is generally preferred that the humidifying of thecollagen carrier is performed when a humidified collaged carrier mayproceed directly to coiling without any intermediate storing as waitingtime for the humidified non-coiled and non-compressed collagen carriermay jeopardise the structural cohesion of the collagen carrier.

Coiled Collagen Carrier

As outlined above, the processes and apparatuses are used to produceform-stable coiled collagen carrier 1. The processes and apparatusesdisclosed above have proven to be efficient to produce the coiledcollagen carrier 1.

Thus, the present invention provides a coiled collagen carrier 1 havinga collagen layer and a coating layer on top of the collagen layer. Thecoating layer comprising mostly solid thrombin and mostly solidfibrinogen although all the thrombin and/or all the fibrinogen may besolid.

The coiled collagen carrier has typically the shape of an elongatedelement with a number of windings of the collagen carrier 3 about thelongitudinal axis of the elongate element and at least the outerwindings and preferably each winding being orientated so that thecoating layer constitutes the outer surface of each of the windings. Afurther characteristic of the coiled collagen carrier 1 is that it isform-stable and defines a collagen carrier in a coiled configurationwhere at least the outer windings proceed along a spiral in a crosssection of the collagen carrier.

The form-stability is often provided by the collagen layer and/or thecoating layer has hardened in the coiled shape whereby no additionalelements such as constraints are needed to keep the coiled collagencarrier in its coiled shape.

The coiled collagen carrier 1 is in an unrolled configuration arectangular sheet, preferably having a width, a length and a thicknessof the most 4 mm, such as at the most 5 mm, preferably at the most 6 mm,such as at the most 7 mm. The coiled collagen carrier is typicallycoiled around the width so that the width of the coiled collagen carrier1 is the width of the unrolled configuration. However coiled collagencarriers being coiled around the length are also an option. A coiledcollagen carrier will often comprise three, four or five windings.

A preferred coiled collagen carrier 1 has a cylindrical shape with anouter diameter of less than 12 mm, such as less than 11 mm, such as lessthan 10 mm, such as less than 9 mm, such as less than 8 mm, such as lessthan 7 mm, such as less than 6 mm, such as less than 5 mm, such as lessthan 4 mm, such as less than 3 mm. Furthermore, the coiled collagencarrier has an s-shaped inner most winding about the longitudinaldirection of the coiled collagen carrier as disclosed e.g. in FIG. 1.

The coating layer of coiled collagen carriers 1 has no through-goingcracks. Often this is obtained by producing the coiled collagen carrierin a manner where the coating layer and/or the collagen layer is(are)softened by humidification prior to coiling which softening allowsstretching of the coating layer and/or collagen layer without producingcrack or chips (frissures) during coiling. A subsequent drying hardensthe softened layer which fixes the coil shape in a form-stable shape.Preferably the coating layer is humidified.

The coiled collagen carrier 1 is often arranged in a container. Thecontainer is typically sealed to prevent contamination and/ordegradation and/or to maintain form-stability of the coiled collagencarrier. A desiccant, such as silica gel, may be arranged in thecontainer. Such containers with coiled collagen carrier 1 is consideredwithin the scope of the invention

In a particular preferred embodiment, a packed coiled collagen carrier 1comprising an inner container and an outer container is provided. Theinner container comprises a compartment having a bottom shaped as asegment of a cylinder, and wherein the curved part of the cylindersegment extends at least 180° as disclosed in FIG. 1 numeral 8. Thecavity is sealed by a tear-off, pull-off or breakable foil and the outercontainer comprising a sealed pouch inside which the sealed innercontainer is arranged together with a desiccant.

FIG. 6 shows a photograph of a coiled collagen carrier 1 arranged in acompartment 27 of an inner container 24 with a cover 25 being partlyremoved. The four cavities 26 are not used for storing any elements butprotrude evenly downwardly and provide four legs to enable stablestanding on a surface.

FIG. 7 shows a photograph a three coiled collagen carriers arrangedside-by-side on a flat surface. The coiled collagen carriers shown inFIGS. 6 and 7 are produced according to the invention as disclosedherein.

Although the present invention has been described in connection with thespecified embodiments, it should not be construed as being in any waylimited to the presented examples. The scope of the present invention isset out by the accompanying claim set. In the context of the claims, theterms “comprising” or “comprises” do not exclude other possible elementsor steps. Also, the mentioning of references such as “a” or “an” etc.should not be construed as excluding a plurality. The use of referencesigns in the claims with respect to elements indicated in the figuresshall also not be construed as limiting the scope of the invention.Furthermore, individual features mentioned in different claims, maypossibly be advantageously combined, and the mentioning of thesefeatures in different claims does not exclude that a combination offeatures is not possible and advantageous.

1-51. (canceled)
 52. A process for coiling a collagen carrier comprising(i) a collagen layer and (ii) a coating layer comprising fibrinogen andthrombin, said process comprising the sequential steps of: humidifyingat least part of said collagen carrier, coiling said collagen carrierdrying the coiled collagen carrier, so as to provide a form-stablecoiled collagen carrier configured for application to a patient.
 53. Theprocess according to claim 52, wherein at least the coating layer ofsaid collagen carrier is humidified.
 54. The process according to claim53, wherein the coating layer has been humidified using a solvent. 55.The process according to claim 54, wherein the collagen carrier ishumidified on the coating layer by a solvent in an amount 1.2-10.75mg/cm² surface of the coating layer.
 56. The process according to 54,wherein the solvent comprises or consists of ethanol.
 57. The processaccording to claim 52, wherein the collagen carrier is compressedsubsequently to humidifying and prior to coiling with a compressionratio between 6-12.
 58. The process according to claim 52, furthercomprising arranging the form-stable coiled collagen carrier in an innercontainer.
 59. The process according to claim 58, further comprisingclosing the inner container by applying a cover to the inner container.60. The process according to claim 59, further comprising arranging theinner ontainer in an outer container, and sealing the outer container.61. The process according to claim 60, wherein the arranging of theform-stable coiled collagen carrier in the inner container and closinginner container is performed in a primary production room and thearranging of the inner container in an outer container is performed in asecondary production room; the first and the secondary production roombe connected with each other by an airlock and the closed innercontainer is transported from the first to the second room via theairlock.
 62. The process according to claim 52, further comprisingsterilizing the coiled collagen carrier.
 63. The process according toclaim 52, wherein the process is carried out as an assembly-line processin which the collagen carrier is conveyed without intermediate storingbetween humidifying and coiling and between coiling and drying.